Title:
Single Nucleotide Polymorphisms as Prognostic Tool to Diagnose Adverse Drug Reactions (Adr) and Drug Efficacy
Kind Code:
A1


Abstract:
The invention provides diagnostic methods and kits including oligo and/or polynucleotides or derivatives, including as well antibodies determining whether a human subject is at risk of getting adverse drug reaction after statin therapy or whether the human subject is a high or low responder or a good a or bad metabolizer of statins. The invention provides further diagnostic methods and kits including antibodies determining whether a human subject is at risk for a cardiovascular disease. Still further the invention provides polymorphic sequences and other genes. The present invention further relates to isolated polynucleotides encoding a phenotype associated (PA) gene polypeptide useful in methods to identify therapeutic agents and useful for preparation of a medicament to treat cardiovascular disease or influence drug response, the polynucleotide is selected from the group comprising: SEQ ID 1-131 with allelic variation as indicated in the sequences section contained in a functional surrounding like full length cDNA for PA gene polypeptide and with or without the PA gene promoter sequence. Sequences: The sequence section contains all phenotype associated (‘PA’) SNPs and adjacent genomic sequences. The position of the polymorphisms that were used for the association studies (‘baySNP’) is indicated. Sometimes additional variations are found in the surrounding genomic sequence, that are marked by it's respective IUPAC code. Although those surrounding SNPs were not explicitly analyzed, they likely exhibit a similar association to a phenotype as the baySNP (due to linkage disequilibrium, Reich D. E. et al. Nature 411, 199-204, 2001).



Inventors:
Stropp, Udo (Haan, DE)
Schwers, Stephen (Koln, DE)
Kallabis, Harald (Koln, DE)
Application Number:
11/572039
Publication Date:
11/15/2007
Filing Date:
07/13/2005
Assignee:
BAYER HEALTHCARE AG (LEVERKUSEN, DE)
Primary Class:
Other Classes:
435/6.11, 435/70.1, 435/254.11, 435/254.2, 435/325, 435/410, 530/300, 536/23.1
International Classes:
A61K31/7088; A61P9/00; C07H21/04; C07K2/00; C12N1/15; C12N1/19; C12N5/10; C12N15/63; C12P21/00; C12Q1/68
View Patent Images:



Primary Examiner:
SALMON, KATHERINE D
Attorney, Agent or Firm:
SIEMENS CORPORATION (Orlando, FL, US)
Claims:
1. An isolated polynucleotide encoded by a phenotype associated (PA) gene; the polynucleotide is selected from the group comprising SEQ ID 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 with allelic variation as indicated in the sequences section contained in a functional surrounding like full length cDNA for PA gene polypeptide and with or without the PA gene promoter sequence.

2. An expression vector containing one or more of the polynucleotides of claim 1.

3. A host cell containing the expression vector of claim 2.

4. A substantially purified PA gene polypeptide encoded by a polynucleotide of claim 1.

5. A method for producing a PA gene polypeptide, wherein the method comprises the following steps: a) culturing the host cell of claim 3 under conditions suitable for the expression of the PA gene polypeptide; and b) recovering the PA gene polypeptide from the host cell culture.

6. A method for the detection of a polynucleotide of claim 1 or a PA gene polypeptide of claim 4 comprising the steps of: contacting a biological sample with a reagent which specifically interacts with the polynucleotide or the PA gene polypeptide.

7. A method of screening for agents which regulate the activity of a PA gene comprising the steps of: contacting a test compound with a PA gene polypeptide encoded by any polynucleotide of claim 1; and detecting PA gene activity of the polypeptide, wherein a test compound which increases the PA gene polypeptide activity is identified as a potential therapeutic agent for increasing the activity of the PA gene polypeptide and wherein a test compound which decreases the PA activity of the polypeptide is identified as a potential therapeutic agent for decreasing the activity of the PA gene polypeptide.

8. A reagent that modulates the activity of a PA polypeptide or a polynucleotide wherein said reagent is identified by the method of the claim 7.

9. A pharmaceutical composition, comprising: the expression vector of claim 2 or the reagent of claim 8 and a pharmaceutically acceptable carrier.

10. Use of the reagent according to claim 8 for the preparation of a medicament.

11. A method for determining whether a human subject has, or is at risk of developing a cardiovascular disease, comprising determining the identity of nucleotide variations as indicated in the sequences section of SEQ ID 1-131 of the PA gene locus of the subject and where the SNP class of the SNP is “CVD” as can be seen from table 3; whereas a “risk” genotype has a risk ratio of greater than 1 as can be seen from table 6.

12. A method for determining a patient's individual response to statin therapy, including drug efficacy and adverse drug reactions, comprising determining the identity of nucleotide variations as indicated in the sequences section of SEQ ID 1-131 of the PA gene locus of the subject and where the SNP class of the SNP is “ADR”, “EFF” or both as can be seen from table 3; whereas the probability for such response can be seen from table 6.

13. Use of the method according to claim 12 for the preparation of a medicament tailored to suit a patient's individual response to statin therapy.

14. A kit for assessing cardiovascular status or statin response, said kit comprising a) sequence determination primers and b) sequence determination reagents, wherein said primers are selected from the group comprising primers that hybridize to polymorphic positions in human PA genes according to claim 1; and primers that hybridize immediately adjacent to polymorphic positions in human PA genes according to claim 1.

15. A kit as defined in claim 12 detecting a combination of two or more, up to all, poly-morphic sites selected from the groups of sequences as defined in claim 1.

16. A kit for assessing cardiovascular status or statin response, said kit comprising one or more antibodies specific for a polymorphic position defined in claim 1 within the human PA gene polypeptides and combinations of any of the foregoing.

Description:

TECHNICAL FIELD

This invention relates to genetic polymorphisms useful for assessing the response to lipid lowering drug therapy and adverse drug reactions of those medicaments. In addition it relates to genetic polymorphisms useful for assessing cardiovascular risks in humans, including, but not limited to, atherosclerosis, ischemia/reperfusion, hypertension, restenosis, arterial inflammation, myocardial infarction, and stroke. Specifically, the present invention identifies and describes gene variations which are individually present in humans with cardiovascular disease states, relative to humans with normal, or non-cardiovascular disease states, and/or in response to medications relevant to cardiovascular disease. Further, the present invention provides methods for the identification and therapeutic use of compounds as treatments of cardiovascular disease or as prophylactic therapy for cardiovascular diseases. Moreover, the present invention provides methods for the diagnostic monitoring of patients undergoing clinical evaluation for the treatment of cardiovascular disease, and for monitoring the efficacy of compounds in clinical trials. Still further, the present invention provides methods to use gene variations to predict personal medication schemes omitting adverse drug reactions and allowing an adjustment of the drug dose to achieve maximum benefit for the patient. Additionally, the present invention describes methods for the diagnostic evaluation and prognosis of various cardiovascular diseases, and for the identification of subjects exhibiting a predisposition to such conditions.

BACKGROUND OF THE INVENTION

Cardiovascular disease is a major health risk throughout the industrialized world.

Cardiovascular diseases include but are not limited by the following disorders of the heart and the vascular system: congestive heart failure, myocardial infarction, atherosclerosis, ischemic diseases of the heart, coronary heart disease, all kinds of atrial and ventricular arrhythmias, hypertensive vascular diseases and peripheral vascular diseases.

Heart failure is defined as a pathophysiologic state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with the requirement of the metabolizing tissue. It includes all forms of pumping failure such as high-output and low-output, acute and chronic, right-sided or left-sided, systolic or diastolic, independent of the underlying cause.

Myocardial infarction (MI) is generally caused by an abrupt decrease in coronary blood flow that follows a thrombotic occlusion of a coronary artery previously narrowed by arteriosclerosis. MI prophylaxis (primary and secondary prevention) is included as well as the acute treatment of MI and the prevention of complications.

Ischemic diseases are conditions in which the coronary flow is restricted resulting in an perfusion which is inadequate to meet the myocardial requirement for oxygen. This group of diseases include stable angina, unstable angina and asymptomatic ischemia.

Arrhythmias include all forms of atrial and ventricular tachyarrhythmias (atrial tachycardia, atrial flutter, atrial fibrillation, atrio-ventricular reentrant tachycardia, preexitation syndrome, ventricular tachycardia, ventricular flutter, ventricular fibrillation) as well as bradycardic forms of arrhythmias.

Hypertensive vascular diseases include primary as well as all kinds of secondary arterial hypertension (renal, endocrine, neurogenic, others).

Peripheral vascular diseases are defined as vascular diseases in which arterial and/or venous flow is reduced resulting in an imbalance between blood supply and tissue oxygen demand. It includes chronic peripheral arterial occlusive disease (PAOD), acute arterial thrombosis and embolism, inflammatory vascular disorders, Raynaud's phenomenon and venous disorders.

Atherosclerosis, the most prevalent of vascular diseases, is the principal cause of heart attack, stroke, and gangrene of the extremities, and thereby the principal cause of death. Atherosclerosis is a complex disease involving many cell types and molecular factors (for a detailed review, see Ross, 1993, Nature 362: 801-809 and Lusis, A. J., Nature 407, 233-241 (2000)). The process, in normal circumstances a protective response to insults to the endothelium and smooth muscle cells (SMCs) of the wall of the artery, consists of the formation of fibrofatty and fibrous lesions or plaques, preceded and accompanied by inflammation. The advanced lesions of atherosclerosis may occlude the artery concerned, and result from an excessive inflammatory-fibroproliferative response to numerous different forms of insult. For example, shear stresses are thought to be responsible for the frequent occurrence of atherosclerotic plaques in regions of the circulatory system where turbulent blood flow occurs, such as branch points and irregular structures.

The first observable event in the formation of an atherosclerotic plaque occurs when blood-borne monocytes adhere to the vascular endothelial layer and transmigrate through to the sub-endothelial space. Adjacent endothelial cells at the same time produce oxidized low density lipoprotein (LDL). These oxidized LDLs are then taken up in large amounts by the monocytes through scavenger receptors expressed on their surfaces. In contrast to the regulated pathway by which native LDL (nLDL) is taken up by nLDL specific receptors, the scavenger pathway of uptake is not regulated by the monocytes.

These lipid-filled monocytes are called foam cells, and are the major constituent of the fatty streak. Interactions between foam cells and the endothelial and SMCs which surround them lead to a state of chronic local inflammation which can eventually lead to smooth muscle cell proliferation and migration, and the formation of a fibrous plaque. Such plaques occlude the blood vessel concerned and thus restrict the flow of blood, resulting in ischemia.

Ischemia is a condition characterized by a lack of oxygen supply in tissues of organs due to inadequate perfusion. Such inadequate perfusion can have number of natural causes, including atherosclerotic or restenotic lesions, anemia, or stroke, to name a few. Many medical interventions, such as the interruption of the flow of blood during bypass surgery, for example, also lead to ischemia. In addition to sometimes being caused by diseased cardiovascular tissue, ischemia may sometimes affect cardiovascular tissue, such as in ischemic heart disease. Ischemia may occur in any organ, however, that is suffering a lack of oxygen supply.

The most common cause of ischemia in the heart is atherosclerotic disease of epicardial coronary arteries. By reducing the lumen of these vessels, atherosclerosis causes an absolute decrease in myocardial perfusion in the basal state or limits appropriate increases in perfusion when the demand for flow is augmented. Coronary blood flow can also be limited by arterial thrombi, spasm, and, rarely, coronary emboli, as well as by ostial narrowing due to luetic aortitis. Congenital abnormalities, such as anomalous origin of the left anterior descending coronary artery from the pulmonary artery, may cause myocardial ischemia and infarction in infancy, but this cause is very rare in adults. Myocardial ischemia can also occur if myocardial oxygen demands are abnormally increased, as in severe ventricular hypertrophy due to hypertension or aortic stenosis. The latter can be present with angina that is indistinguishable from that caused by coronary atherosclerosis. A reduction in the oxygen-carrying capacity of the blood, as in extremely severe anemia or in the presence of carboxy-hemoglobin, is a rare cause of myocardial ischemia. Not infrequently, two or more causes of ischemia will coexist, such as an increase in oxygen demand due to left ventricular hypertrophy and a reduction in oxygen supply secondary to coronary atherosclerosis.

The foregoing studies are aimed at defining the role of particular gene variations presumed to be involved in the misleading of normal cellular function leading to cardiovascular disease. However, such approaches cannot identify the full panoply of gene variations that are involved in the disease process.

At present, the only available treatments for cardiovascular disorders are pharmaceutical based medications that are not targeted to an individual's actual defect; examples include angiotensin converting enzyme (ACE) inhibitors and diuretics for hypertension, insulin supplementation for non-insulin dependent diabetes mellitus (NIDDM), cholesterol reduction strategies for dyslipidaemia, anticoagulants, β blockers for cardiovascular disorders and weight reduction strategies for obesity. If targeted treatment strategies were available it might be possible to predict the response to a particular regime of therapy and could markedly increase the effectiveness of such treatment. Although targeted therapy requires accurate diagnostic tests for disease susceptibility, once these tests are developed the opportunity to utilize targeted therapy will become widespread. Such diagnostic tests could initially serve to identify individuals at most risk of hypertension and could allow them to make changes in lifestyle or diet that would serve as preventative measures. The benefits associated by coupling the diagnostic tests with a system of targeted therapy could include the reduction in dosage of administered drugs and thus the amount of unpleasant side effects suffered by an individual. In more severe cases a diagnostic test may suggest that earlier surgical intervention would be useful in preventing a further deterioration in condition.

It is an object of the invention to provide genetic diagnosis of predisposition or susceptibility for cardiovascular diseases. Another related object is to provide treatment to reduce or prevent or delay the onset of disease in those predisposed or susceptible to this disease. A further object is to provide means for carrying out this diagnosis.

Accordingly, a first aspect of the invention provides a method of diagnosis of disease in an individual, said method comprising determining one, various or all genotypes in said individual of the genes listed in the Examples.

In another aspect, the invention provides a method of identifying an individual predisposed or susceptible to a disease, said method comprising determining one, various or all genotypes in said individual of the genes listed in the Examples.

The invention is of advantage in that it enables diagnosis of a disease or of certain disease states via genetic analysis which can yield useable results before onset of disease symptoms, or before onset of severe symptoms. The invention is further of advantage in that it enables diagnosis of predisposition or susceptibility to a disease or of certain disease states via genetic analysis.

The invention may also be of use in confirming or corroborating the results of other diagnostic methods. The diagnosis of the invention may thus suitably be used either as an isolated technique or in combination with other methods and apparatus for diagnosis, in which latter case the invention provides a further test on which a diagnosis may be assessed.

The present invention stems from using allelic association as a method for genotyping individuals; allowing the investigation of the molecular genetic basis for cardiovascular diseases. In a specific embodiment the invention tests for the polymorphisms in the sequences of the listed genes in the Examples. The invention demonstrates a link between this polymorphisms and predispositions to cardiovascular diseases by showing that allele frequencies significantly differ when individuals with “bad” serum lipids are compared to individuals with “good” serum levels. The meaning of “good and bad” serum lipid levels is defined in Table 1a.

Certain disease states would benefit, that is to say the suffering of the patient may be reduced or prevented or delayed, by administration of treatment or therapy in advance of disease appearance; this can be more reliably carried out if advance diagnosis of predisposition or susceptibility to disease can be diagnosed.

Pharmacogenomics and Adverse Drug Reactions

Adverse drug reactions (ADRs) remain a major clinical problem. A recent meta-analysis suggested that in the USA in 1994, ADRs were responsible for 100000 deaths, making them between the fourth and sixth commonest cause of death (Lazarou 1998, J. Am. Med. Assoc. 279:1200). Although these figures have been heavily criticized, they emphasize the importance of ADRs. Indeed, there is good evidence that ADRs account for 5% of all hospital admissions and increase the length of stay in hospital by two days at an increased cost of ˜$2500 per patient. ADRs are also one of the commonest causes of drug withdrawal, which has enormous financial implications for the pharmaceutical industry. ADRs, perhaps fortunately, only affect a minority of those taking a particular drug. Although factors that determine susceptibility are unclear in most cases, there is increasing interest in the role of genetic factors. Indeed, the role of inheritable variations in predisposing patients to ADRs has been appreciated since the late 1950s and early 1960s through the discovery of deficiencies in enzymes such as pseudocholinesterase (butyrylcholinesterase) and glucose-6-phosphate dehydrogenase (G6PD). More recently, with the first draft of the human genome just completed, there has been renewed interest in this area with the introduction of terms such as pharmacogenomics and toxicogenomics. Essentially, the aim of pharmacogenomics and pharmacogenetics is to produce personalized medicines, whereby administration of the drug class and dosage is tailored to an individual genotype. Thus, the term pharmacogenetics embraces both efficacy and toxicity.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (“statins”) specifically inhibit the enzyme HMG-CoA reductase which catalyzes the rate limiting step in cholesterol biosynthesis. These drugs are effective in reducing the primary and secondary risk of coronary artery disease and coronary events, such as heart attack, in middle-aged and older men and women, in both diabetic and non-diabetic patients, and are often prescribed for patients with hyperlipidemia. Statins used in secondary prevention of coronary artery or heart disease significantly reduce the risk of stroke, total mortality and morbidity and attacks of myocardial ischemia; the use of statins is also associated with improvements in endothelial and fibrinolytic functions and decreased platelet thrombus formation.

The tolerability of these drugs during long term administration is an important issue. Adverse reactions involving skeletal muscle are not uncommon, and sometimes serious adverse reactions involving skeletal muscle such as myopathy and rhabdomyolysis may occur, requiring discontinuation of the drug. In addition an increase in serum creatine kinase (CK) may be a sign of a statin related adverse event. The extend of such adverse events can be read from the extend of the CK level increase (as compared to the upper limit of normal [ULN]).

Occasionally arthralgia, alone or in association with myalgia, has been reported. Also an elevation of liver transaminases has been associated with statin administration.

It was shown that the drug response to statin therapy is a class effects, i.e. all known and presumably also all so far undiscovered statins share the same beneficial and harmful effects (Ucar, M. et al., Drug Safety 2000, 22:441). It follows that the discovery of diagnostic tools to predict the drug response to a single statin will also be of aid to guide therapy with other statins.

The present invention provides diagnostic tests to predict the patient's individual response to statin therapy. Such responses include, but are not limited by the extent of adverse drug reactions, the level of lipid lowering or the drug's influence on disease states. Those diagnostic tests may predict the response to statin therapy either alone or in combination with another diagnostic test or another drug regimen.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based at least in part on the discovery that a specific allele of a polymorphic region of a so called “candidate gene” (as defined below) is associated with CVD or drug response.

For the present invention the following candidate genes were analyzed:

    • Genes found to be expressed in cardiac tissue (Hwang et al., Circulation 1997, 96:4146-4203).
    • Genes from the following metabolic pathways and their regulatory elements:

Lipid Metabolism

Numerous studies have shown a connection between serum lipid levels and cardiovascular diseases. Candidate genes falling into this group include but are not limited by genes of the cholesterol pathway, apolipoproteins and their modifying factors.

Coagulation

Ischemic diseases of the heart and in particular myocardial infarction may be caused by a thrombotic occlusion. Genes falling into this group include all genes of the coagulation cascade and their regulatory elements.

Inflammation

Complications of atherosclerosis are the most common causes of death in Western societies. In broad outline atherosclerosis can be considered to be a form of chronic inflammation resulting from interaction modified lipoproteins, monocyte-derived macrophages, T cells, and the normal cellular elements of the arterial wall. This inflammatory process can ultimately lead to the development of complex lesions, or plaques, that protrude into the arterial lumen. Finally plaque rupture and thrombosis result in the acute clinical complications of myocardial infarction and stroke (Glass et al., Cell 2001, 104:503-516).

It follows that all genes related to inflammatory processes, including but not limited by cytokines, cytokine receptors and cell adhesion molecules are candidate genes for CVD.

Glucose and Energy Metabolism

As glucose and energy metabolism is interdependent with the metabolism of lipids (see above) also the former pathways contain candidate genes. Energy metabolism in general also relates to obesity, which is an independent risk factor for CVD (Melanson et al., Cardiol Rev 2001 9:202-207). In addition high blood glucose levels are associated with many microvascular and macrovascular complications and may therefore affect an individuals disposition to CVD (Duckworth, Curr Atheroscler Rep 2001, 3:383-391).

Hypertension

As hypertension is an independent risk factor for CVD, also genes that are involved in the regulation of systolic and diastolic blood pressure affect an individuals risk for CVD (Safar, Curr Opin Cardiol 2000, 15:258-263). Interestingly hypertension and diabetes (see above) appear to be interdependent, since hypertension is approximately twice as frequent in patients with diabetes compared with patients without the disease. Conversely, recent data suggest that hypertensive persons are more predisposed to the development of diabetes than are normotensive persons (Sowers et al., Hypertension 2001, 37:1053-1059).

Genes Related to Drug Response

Those genes include metabolic pathways involved in the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. Prominent members of this group are the cytochrome P450 proteins which catalyze many reactions involved in drug metabolism.

Unclassified Genes

As stated above, the mechanisms that lead to cardiovascular diseases or define the patient's individual response to drugs are not completely elucidated. Hence also candidate genes were analysed, which could not be assigned to the above listed categories. The present invention is based at least in part on the discovery of polymorphisms, that lie in genomic regions of unknown physiological function.

Results

After conducting an association study, we surprisingly found polymorphic sites in a number of candidate genes which show a strong correlation with the following phenotypes of the patients analysed: “Healthy” as used herein refers to individuals that neither suffer from existing CVD, nor exhibit an increased risk for CVD through their serum lipid level profile. “CVD prone” as used herein refers to individuals with existing CVD and/or a serum lipid profile that confers a high risk to get CVD (see Table 1a for definitions of healthy and CVD prone serum lipid levels). “High responder” as used herein refers to patients who benefit from relatively small amounts of a given drug. “Low responder” as used herein refers to patients who need relatively high doses in order to obtain benefit from the medication. “Tolerant patient” refers to individuals who can tolerate high doses of a medicament without exhibiting adverse drug reactions. “ADR patient” as used herein refers to individuals who suffer from ADR or show clinical symptoms (like creatine kinase elevation in blood) even after receiving only minor doses of a medicament (see Table 1b for a detailed definition of drug response phenotypes).

Polymorphic sites in candidate genes that were found to be significantly associated with either of the above mentioned phenotypes will be referred to as “phenotype associated SNPs” (PA SNPs). The respective genomic loci that harbour PA SNPs will be referred to as “phenotype associated genes” (PA genes), irrespective of the actual function of this gene locus.

In particular we surprisingly found PA SNPs associated with CVD, drug efficacy (EFF) or adverse drug reactions (ADR) in the following genes:

ABCA1: ATP-Binding Cassette, Sub-Family A (ABC1), Member 1

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. With cholesterol as its substrate, this protein functions as a cholesterol efflux pump in the cellular lipid removal pathway. Mutations in this gene have been associated with Tangier's disease and familial high-density lipoprotein deficiency.

ABCB1: ATP-Binding Cassette, Sub-Family B (MDR/TAP), Member 1

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. It is responsible for decreased drug accumulation in multidrug-resistant cells and often mediates the development of resistance to anticancer drugs. This protein also functions as a transporter in the blood-brain barrier.

ACACB: Acetyl-Coenzyme A Carboxylase Beta

Acetyl-CoA carboxylase (ACC) is a complex multifunctional enzyme system. ACC is a biotin-containing enzyme which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis. ACC-beta is thought to control fatty acid oxidation by means of the ability of malonyl-CoA to inhibit carnitine-palmitoyl-CoA transferase I, the rate-limiting step in fatty acid uptake and oxidation by mitochondria. ACC-beta may be involved in the regulation of fatty acid oxidation, rather than fatty acid biosynthesis. There is evidence for the presence of two ACC-beta isoforms.

ADRB3: Adrenergic, Beta-3-, Receptor

The ADRB3 gene product, beta-3-adrenergic receptor, is located mainly in adipose tissue and is involved in the regulation of lipolysis and thermogenesis. Beta adrenergic receptors are involved in the epenephrine and norepinephrine-induced activation of adenylate cyclase through the action of G proteins.

AKAP1: A Kinase (PRKA) Anchor Protein 1

The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. Alternative splicing of this gene results in 2 transcript variants encoding 2 isoforms with different sizes. Both of the isoforms bind to types I and R regulatory subunits of PKA and anchor them to mitochondria. As compared to the longer isoform, the shorter isoform lacks a K-homologous motif, which is an RNA-binding domain typically associated with proteins involved in RNA catalysis, mRNA processing, or translation. The longer isoform is speculated to be involved in the cAMP-dependent signal transduction pathway and in directing RNA to a specific cellular compartment. The function of the shorter isoform has not been determined.

AKAP10: A Kinase (PRKA) Anchor Protein 10

The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein interacts with both the type I and type II regulatory subunits of PKA; therefore, it is a dual-specific AKAP. This protein is highly enriched in mitochondria. It contains RGS (regulator of G protein signalling) domains, in addition to a PKA-RII subunit-binding domain. The mitochondrial localization and the presence of RGS domains may have important implications for the function of this protein in PKA and G protein signal transduction.

AKAP13: A Kinase (PRKA) Anchor Protein 13

The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. Alternative splicing of this gene results in at least 3 transcript variants encoding different isoforms containing a dbI oncogene homology (DH) domain and a pleckstrin homology (PH) domain. The DH domain is associated with guanine nucleotide exchange activation for the Rho/Rac family of small GTP binding proteins, resulting in the conversion of the inactive GTPase to the active form capable of transducing signals. The PH domain has multiple functions. Therefore, these isoforms function as scaffolding proteins to coordinate a Rho signaling pathway and, in addition, function as protein kinase A-anchoring proteins.

AMPD1: Adenosine Monophosphate Deaminase 1 (Isoform M)

Adenosine monophosphate deaminase 1 catalyzes the deamination of AMP to IMP in skeletal muscle and plays an important role in the purine nucleotide cycle. Two other genes have been identified, AMPD2 and AMPD3, for the liver- and erythocyte-specific isoforms, respectively. Deficiency of the muscle-specific enzyme is apparently a common cause of exercise-induced myopathy and probably the most common cause of metabolic myopathy in the human.

APOE: Apolipoprotein E

Chylomicron remnants and very low density lipoprotein (VLDL) remnants are rapidly removed from the circulation by receptor-mediated endocytosis in the liver. Apolipoprotein E, a main apoprotein of the chylomicron, binds to a specific receptor on liver cells and peripheral cells. ApoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. The APOE gene is mapped to chromosome 19 in a cluster with APOC1 and APOC2. Defects in apolipoprotein E result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants.

APOM: Apolipoprotein M

The protein encoded by this gene is an apolipoprotein and member of the lipocalin protein family. It is found associated with high density lipoproteins and to a lesser extent with low density lipoproteins and triglyceride-rich lipoproteins. The encoded protein is secreted through the plasma membrane but remains membrane-bound, where it is involved in lipid transport. Two transcript variants encoding two different isoforms have been found for this gene, but only one of them has been fully characterized.

ARHGAP1: Rho GTPase Activating Protein 1

GTPase-activating protein for rho, rac and Cdc42Hs; has an SH3 binding domain

ATP1A2: ATPase, Na+/K+ Transporting, Alpha 2 (+) Polypeptide

ATP2A1: ATPase, Ca++ Transporting, Cardiac Muscle, Fast Twitch 1

This gene encodes one of the SERCA Ca (2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of muscle cells. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen, and is involved in muscular excitation and contraction. Mutations in this gene cause some autosomal recessive forms of Brody disease, characterized by increasing impairment of muscular relaxation during exercise. Alternative splicing results in two transcript variants encoding different isoforms.

BAT3: HLA-B Associated Transcript 3

A cluster of genes, BAT1-BAT5, has been localized in the vicinity of the genes for TNF alpha and TNF beta. These genes are all within the human major histocompatibility complex class III region. The protein encoded by this gene is a nuclear protein. It has been implicated in the control of apoptosis and regulating heat shock protein. There are three alternatively spliced transcript variants described for this gene.

BAT4: HLA-B Associated Transcript 4

A cluster of genes, BAT1-BAT5, has been localized in the vicinity of the genes for TNF alpha and TNF beta. These genes are all within the human major histocompatibility complex class III region. The protein encoded by this gene is thought to be involved in some aspects of immunity.

BAT5: HLA-B Associated Transcript 5

A cluster of genes, BAT1-BAT5, has been localized in the vicinity of the genes for TNF alpha and TNF beta. These genes are all within the human major histocompatibility complex class III region. The protein encoded by this gene is thought to be involved in some aspects of immunity.

BRD3: Bromodomain Containing 3

This gene was identified based on its homology to the gene encoding the RING3 protein, a serine/threonine kinase. The gene localizes to 9q34, a region which contains several major histocompatibility complex (MHC) genes. The function of the encoded protein is not known.

CDC42BPB: CDC42 Binding Protein Kinase Beta (DMPK-Like)

The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein contains a Cdc42/Rac-binding p21 binding domain resembling that of PAK kinase. The kinase domain of this protein is most closely related to that of myotonic dystrophy kinase-related ROK. Studies of the similar gene in rat suggested that this kinase may act as a downstream effector of Cdc42 in cytoskeletal reorganization.

CDC42EP2: CDC42 Effector Protein (Rho GTPase Binding) 2

CDC42, a small Rho GTPase, regulates the formation of F-actin-containing structures through its interaction with the downstream effector proteins. The protein encoded by this gene is a member of the Borg family of CDC42 effector proteins. Borg family proteins contain a CRIB (Cdc42/Rac interactive-binding) domain. They bind to, and negatively regulate the function of, CDC42. Coexpression of this protein with dominant negative mutant CDC42 protein in fibroblast was found to induce pseudopodia formation, which suggested a role of this protein in actin filament assembly and cell shape control.

CDC42EP3: CDC42 Effector Protein (Rho GTPase Binding) 3

CDC42, a small Rho GTPase, regulates the formation of F-actin-containing structures through its interaction with the downstream effector proteins. The protein encoded by this gene is a member of the Borg family of CDC42 effector proteins. Borg family proteins contain a CRIB (Cdc42/Rac interactive-binding) domain. They bind to, and negatively regulate the function of, CDC42. This protein can interact with CDC42, as well as with the ras homolog gene family, member Q (ARHQ/TC10). Expression of this protein in fibroblasts has been shown to induce pseudopodia formation.

CDC42EP4: CDC42 Effector Protein (Rho GTPase Binding) 4

The product of this gene is a member of the CDC42-binding protein family. Members of this family interact with Rho family GTPases and regulate the organization of the actin cytoskeleton. This protein has been shown to bind both CDC42 and TC10 GTPases in a GTP-dependent manner. When overexpressed in fibroblasts, this protein was able to induce pseudopodia formation, which suggested a role in inducing actin filament assembly and cell shape control.

CENPC1: Centromere Protein C 1

Centromere protein C 1 is a centromere autoantigen and a component of the inner kinetochore plate. The protein is required for maintaining proper kinetochore size and a timely transition to anaphase. A putative psuedogene exists on chromosome 12.

CETP: Cholesteryl Ester Transfer Protein, Plasma

Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters between lipoproteins. CETP may effect susceptibility to atherosclerosis.

CPB2: Carboxypeptidase B2 (Plasma, Carboxypeptidase U)

Carboxypeptidases are enzymes that hydrolyze C-terminal peptide bonds. The carboxypeptidase family includes metallo-, serine, and cysteine carboxypeptidases. According to their substrate specificity, these enzymes are referred to as carboxypeptidase A (cleaving aliphatic residues) or carboxypeptidase B (cleaving basic amino residues). The protein encoded by this gene is activated by trypsin and acts on carboxypeptidase B substrates. After thrombin activation, the mature protein downregulates fibrinolysis. Polymorphisms have been described for this gene and its promoter region. Available sequence data analyses indicate splice variants that encode different isoforms.

CROT: Carnitine O-Octanoyltransferase

CSF2: Colony Stimulating Factor 2 (Granulocyte-Macrophage) IL3: Interleukin 3 (Colony-Stimulating Factor, Multiple)

The protein encoded by this gene is a cytokine that controls the production, differentiation, and function of granulocytes and macrophages. The active form of the protein is found extracellularly as a homodimer. This gene has been localized to a cluster of related genes at chromosome region 5q31, which is known to be associated with interstitial deletions in the 5q-syndrome and acute myelogenous leukemia. Other genes in the cluster include those encoding interleukins 4, 5, and 13.

DFNA5: Deafness, Autosomal Dominant 5

Hearing impairment is a heterogeneous condition with over 40 loci described. The protein encoded by this gene is expressed in fetal cochlea, however, its function is not known. Nonsyndromic hearing impairment is associated with a mutation in this gene.

F2: Coagulation Factor II (Thrombin)

Coagulation factor II is proteolytically cleaved to form thrombin in the first step of the coagulation cascade which ultimately results in the stemming of blood loss. F2 also plays a role in maintaining vascular integrity during development and postnatal life. Mutations in F2 leads to various forms of thrombosis and dysprothrombinemia.

FKBP1A: FK506 Binding Protein 1A, 12 kDa

The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. This encoded protein is a cis-trans prolyl isomerase that binds the immunosuppressants FK506 and rapamycin. It interacts with several intracellular signal transduction proteins including type I TGF-beta receptor. It also interacts with multiple intracellular calcium release channels including the tetrameric skeletal muscle ryanodine receptor. In mouse, deletion of this homologous gene causes congenital heart disorder known as noncompaction of left ventricular myocardium. There is evidence of multiple alternatively spliced transcript variants for this gene, but the full length nature of some variants has not been determined.

FYN: FYN Oncogene Related to SRC, FGR, YES

This gene is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth. The protein associates with the p85 subunit of phosphatidylinositol 3-kinase and interacts with the fyn-binding protein. Alternatively spliced transcript variants encoding distinct isoforms exist.

GHR: Growth Hormone Receptor

Biologically active growth hormone (MIM 139250) binds its transmembrane receptor (GHR), which dimerizes to activate an intracellular signal transduction pathway leading to synthesis and secretion of insulin-like growth factor I (IGF1; MIM 147440). In plasma, IGF1 binds to the soluble IGF1 receptor (IGF1R; MIM 147370). At target cells, this complex activates signal-transduction pathways that result in the mitogenic and anabolic responses that lead to growth. [supplied by OMIM]

HSPA9B: Heat Shock 70 kDa Protein 9B (Mortalin-2)

The product encoded by this gene belongs to the heat shock protein 70 family which contains both heat-inducible and constitutively expressed members. The latter are called heat-shock cognate proteins. This gene encodes a heat-shock cognate protein. This protein plays a role in the control of cell proliferation. It may also act as a chaperone.

IQGAP1: IQ Motif Containing GTPase Activating Protein 1

IQGAP2: IQ Motif Containing GTPase Activating Protein 2

LAG3: Lymphocyte-Activation Gene 3

Lymphocyte-activation protein 3 belongs to Ig superfamily and contains 4 extracellular Ig-like domains. The LAG3 gene contains 8 exons. The sequence data, exon/intron organization, and chromosomal localization all indicate a close relationship of LAG3 to CD4.

LCAT: Lecithin-Cholesterol Acyltransferase

This gene encodes the extracellular cholesterol esterifying enzyme, lecithin-cholesterol acyltransferase. The esterification of cholesterol is required for cholesterol transport. Mutations in this gene have been found to cause fish-eye disease as well as LCAT deficiency.

LCP2: Lymphocyte Cytosolic Protein 2 (SH2 Domain Containing Leukocyte Protein of 76 kDa)

SLP-76 was originally identified as a substrate of the ZAP-70 protein tyrosine kinase following T cell receptor (TCR) ligation in the leukemic T cell line Jurkat. The SLP-76 locus has been localized to human chromosome 5q33 and the gene structure has been partially characterized in mice. The human and murine cDNAs both encode 533 amino acid proteins that are 72% identical and comprised of three modular domains. The NH2-terminus contains an acidic region that includes a PEST domain and several tyrosine residues which are phosphorylated following TCR ligation. SLP-76 also contains a central proline-rich domain and a COOH-terminal SH2 domain. A number of additional proteins have been identified that associate with SLP-76 both constitutively and inducibly following receptor ligation, supporting the notion that SLP-76 functions as an adaptor or scaffold protein. Studies using SLP-76 deficient T cell lines or mice have provided strong evidence that SLP-76 plays a positive role in promoting T cell development and ac

LIF: Leukemia Inhibitory Factor (Cholinergic Differentiation Factor)

Leukaemia inhibitory factor is a cytokine that induces macrophage differentiation. Neurotransmitters and neuropeptides, well known for their role in the communication between neurons, are also capable of activating monocytes and macrophages and inducing chemotaxis in immune cells. LIF signals through different receptors and transcription factors. LIF in conjunction with BMP2 acts in synergy on primary fetal neural progenitor cells to induce astrocytes.

LIMK1: LIM Domain Kinase 1

There are approximately 40 known eukaryotic LIM proteins, so named for the LIM domains they contain. LIM domains are highly conserved cysteine-rich structures containing 2 zinc fingers. Although zinc fingers usually function by binding to DNA or RNA, the LIM motif probably mediates protein-protein interactions. LIM kinase-1 and LIM kinase-2 belong to a small subfamily with a unique combination of 2 N-terminal LIM motifs and a C-terminal protein kinase domain. LIMK1 is likely to be a component of an intracellular signaling pathway and may be involved in brain development. LIMK1 hemizygosity is implicated in the impaired visuospatial constructive cognition of Williams syndrome. Two splice variant have been identified.

LIPA: Lipase A, Lysosomal Acid, Cholesterol Esterase (Wolman Disease)

LIPA encodes lipase A, the lysosomal acid lipase (also known as cholesteryl ester hydrolase). This enzyme functions in the lysosome to catalyze the hydrolysis of cholesteryl esters and triglycerides. Mutations in LIPA can result in Wolman disease and cholesteryl ester storage disease.

LPA: Lipoprotein, Lp(a)

LPL: Lipoprotein Lipase

LPL encodes lipoprotein lipase, which is expressed in heart, muscle, and adipose tissue. LPL functions as a homodimer, and has the dual functions of triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptake. Severe mutations that cause LPL deficiency result in type I hyperlipoproteinemia, while less extreme mutations in LPL are linked to many disorders of lipoprotein metabolism.

LTA: Lymphotoxin Alpha (TNF Superfamily, Member 1)

Lymphotoxin alpha, a member of the tumor necrosis factor family, is a cytokine produced by lymphocytes. LTA is highly inducible, secreted, and exists as homotrimeric molecule. LTA forms heterotrimers with lymphotoxin-beta which anchors lymphotoxin-alpha to the cell surface. LTA mediates a large variety of inflammatory, immunostimulatory, and antiviral responses. LTA is also involved in the formation of secondary lymphoid organs during development and plays a role in apoptosis.

MTND4L: NADH Dehydrogenase 4L

NDUFA6: NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex, 6, 14 kDa

NDUFB10: NADH Dehydrogenase (Ubiquinone) 1 Beta Subcomplex, 10, 22 kDa

Subunit of NADH-ubiquinone oxidoreductase (complex I); transports electrons from NADH to ubiquinone

NDUFB5: NADH Dehydrogenase (Ubiquinone) 1 Beta Subcomplex, 5, 16 kDa

The protein encoded by this gene is a subunit of the multisubunit NADH: ubiquinone oxido-reductase (complex I). Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxido-reductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone.

NDUFC2: NADH Dehydrogenase (Ubiquinone) 1, Subcomplex Unknown, 2, 14.5 kDa

Subunit of NADH-ubiquinone oxidoreductase (complex I); transports electrons from NADH to ubiquinone

NF1: Neurofibromin 1 (Neurofibromatosis, Von Recklinghausen Disease, Watson Disease)

Mutations linked to neurofibromatosis type 1 led to the identification of NF1. NF1 encodes the protein neurofibromin, which appears to be a negative regulator of the ras signal transduction pathway. In addition to type 1 neurofibromatosis, mutations in NF1 can also lead to juvenile myelomonocytic leukemia. Alternatively spliced NF1 mRNA transcripts have been isolated, although their functions, if any, remain unclear.

GRAF: GTPase Regulator Associated with Focal Adhesion Kinase Pp125(FAK)

SPC25: AD024-Protein

TOSO: Regulator of Fas-Induced Apoptosis

ZNF202: Zinc Finger Protein 202

PAK2: P21 (CDKN1A)-Activated Kinase 2

The p21 activated kinases (PAK) are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. The PAK proteins are a family of serine/threonine kinases that serve as targets for the small GTP binding proteins, CDC42 and RAC1, and have been implicated in a wide range of biological activities. The protein encoded by this gene is activated by proteolytic cleavage during caspase-mediated apoptosis, and may play a role in regulating the apoptotic events in the dying cell.

PDCD6IP: Programmed Cell Death 6 Interacting Protein

This gene encodes a protein thought to participate in programmed cell death. Studies using mouse cells have shown that overexpression of this protein can block apoptosis. In addition, the product of this gene binds to the product of the PDCD6 gene, a protein required for apoptosis, in a calcium-dependent manner. This gene product also binds to endophilins, proteins that regulate membrane shape during endocytosis. Overexpression of this gene product and endophilins results in cytoplasmic vacuolization which may be partly responsible for the protection against cell death.

PDE4D: Phosphodiesterase 4D, cAMP-Specific (Phosphodiesterase E3 Dunce Homolog, Drosophila

CAMP-specific phosphodiesterase 4D; has similarity to Drosophila dnc, which is the affected protein in learning and memory mutant dunce

PDGFRA: Platelet-Derived Growth Factor Receptor, Alpha Polypeptide

This gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. These growth factors are mitogens for cells of mesenchymal origin. The identity of the growth factor bound to a receptor monomer determines whether the functional receptor is a homodimer or a heterodimer, composed of both platelet-derived growth factor receptor alpha and beta polypeptides. Studies in knockout mice, where homozygosity is lethal, indicate that the alpha form of the platelet-derived growth factor receptor is particularly important for kidney development since mice heterozygous for the receptor exhibit defective kidney phenotypes.

PFKM: Phosphofructokinase, Muscle

PLA2G4C: Phospholipase A2, Group IVC (Cytosolic, Calcium-Independent)

PLP1: Proteolipid Protein 1 (Pelizaeus-Merzbacher Disease, Spastic Paraplegia 2, Uncomplicated)

PPP1R12C: Protein Phosphatase 1, Regulatory (Inhibitor) Subunit 12C

Low similarity to MYPT2

PRKAR2B: Protein Kinase, Camp-Dependent, Regulatory, Type II, Beta

PRKCB1: Protein Kinase C, Beta 1

PTK2B: PTK2B Protein Tyrosine Kinase 2 Beta

This gene encodes a cytoplasmic protein tyrosine kinase which is involved in calcium-induced regulation of ion channels and activation of the map kinase signaling pathway. The encoded protein may represent an important signaling intermediate between neuropeptide-activated receptors or neurotransmitters that increase calcium flux and the downstrearm signals that regulate neuronal activity. The encoded protein undergoes rapid tyrosine phosphorylation and activation in response to increases in the intracellular calcium concentration, nicotinic acetylcholine receptor activation, membrane depolarization, or protein kinase C activation. This protein has been shown to bind CRK-associated substrate, nephrocystin, GTPase regulator associated with FAK, and the SH2 domain of GRB2. The encoded protein is a member of the FAK subfamily of protein tyrosine kinases but lacks significant sequence similarity to kinases from other subfamilies. Four transcript variants encoding two different isoforms have been found for this gene

PYGM: Phosphorylase, Glycogen; Muscle (McArdle Syndrome, Glycogen Storage Disease Type V)

RABGGTA: Rab Geranylgeranyltransferase, Alpha Subunit

RYR1: Ryanodine Receptor 1 (Skeletal)

RYR3: Ryanodine Receptor 3

SCARB1: Scavenger Receptor Class B, Member 1

SCO2: SCO Cytochrome Oxidase Deficient Homolog 2 (Yeast)

Mammalian cytochrome c oxidase (COX) catalyzes the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. In yeast, 2 related COX assembly genes, SCO1 and SCO2 (synthesis of cytochrome c oxidase), enable subunits 1 and 2 to be incorporated into the holoprotein. This gene is the human homolog of the yeast SCO2 gene.

SELE: Selectin E (Endothelial Adhesion Molecule 1)

The endothelial leukocyte adhesion molecule-1 is expressed by cytokine-stimulated endothelial cells. It is thought to be responsible for the accumulation of blood leukocytes at sites of inflammation by mediating the adhesion of cells to the vascular lining. It exhibits structural features such as the presence of lectin- and EGF-like domains followed by short consensus repeat (SCR) domains that contain 6 conserved cysteine residues. These proteins are part of the selectin family of cell adhesion molecules. This gene is present in single copy in the human genome and contains 14 exons spanning about 13 kb of DNA. Adhesion molecules participate in the interaction between leukocytes and the endothelium and appear to be involved in the pathogenesis of atherosclerosis.

SEPP1: Selenoprotein P, Plasma, 1

Selenoprotein P is an extracellular glycoprotein and is the only selenoprotein known to contain multiple selenocysteine residues. Two isoforms of this protein are Sep51 and Sep61. Sep51 lacks part of the C-terminal sequence. Selenoprotein P binds heparin and associates with endothelial cells. They are implicated as an oxidant defense in the extracellular space and in the transport of selenium.

SERPINA1: Serine (or Cysteine) Proteinase Inhibitor, Clade A (Alpha-1 Antiproteinase, Antitrypsin), Member 1

Alpha-1-antitrypsin is a protease inhibitor, deficiency of which is associated with emphysema and liver disease. The protein is encoded by a gene (PI) located on the distal long arm of chromosome 14. [supplied by OMIM]

SERPINA5: Serine (or Cysteine) Proteinase Inhibitor, Clade A (Alpha-1 Antiproteinase, Antitrypsin), Member 5

SERPINB2: Serine (or Cysteine) Proteinase Inhibitor, Clade B (Ovalbumin), Member 2

SLC6A8: Solute Carrier Family 6 (Neurotransmitter Transporter, Creatine), Member 8

Sodium and chloride-dependent creatine transporter; member of neurotransmitter transporter family

SSA1: Sjogren Syndrome Antigen A1 (52 kDa, Ribonucleoprotein Autoantigen SS-A/Ro)

The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. This protein is part of the RoSSA ribonucleoprotein which includes a single polypeptide and one of four small RNA molecules. The RoSSA particle localizes to both the cytoplasm and the nucleus. RoSSA interacts with autoantigens in patients with Sjogren syndrome and systemic lupus erythematosus. The function of the RoSSA particle has not been determined. Two alternatively spliced transcript variants for this gene have been described; however, the full length nature of one variant has not been determined.

STCH: Stress 70 Protein Chaperone, Microsome-Associated, 60 kDa

SULT1A2: Sulfotransferase Family, Cytosolic, 1A, Phenol-Preferring, Member 2

Sulfotransferase enzymes catalyze the sulfate conjugation of many hormones, neurotransmitters, drugs, and xenobiotic compounds. These cytosolic enzymes are different in their tissue distributions and substrate specificities. The gene structure (number and length of exons) is similar among family members. This gene encodes one of two phenol sulfotransferases with thermostable enzyme activity. Two alternatively spliced variants that encode the same protein have been described.

SYK: Spleen Tyrosine Kinase

TAP1: Transporter 1, ATP-Binding Cassette, Sub-Family B (MDR/TAP)

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is involved in the pumping of degraded cytosolic peptides across the endoplasmic reticulum into the membrane-bound compartment where class I molecules assemble. Mutations in this gene may be associated with ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease.

TAP2: Transporter 2, ATP-Binding Cassette, Sub-Family B (MDR/TAP)

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. This gene is located 7 kb telomeric to gene family member ABCB2. The protein encoded by this gene is involved in antigen presentation. This protein forms a heterodimer with ABCB2 in order to transport peptides from the cytoplasm to the endoplasmic reticulum. Mutations in this gene may be associated with ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease. Alternative splicing of this gene produces two products which differ in peptide selectivity and level of restoration of surface expression of MHC class I molecules.

THBD: Thrombomodulin

TRIM28: Tripartite Motif-Containing 28 LocusID:

TRIP10: Thyroid Hormone Receptor Interactor 10

Similar to the non-kinase domains of FER and Fes/Fps tyrosine kinases; binds to activated Cdc42 and may regulate actin cytoskeleton; contains an SH3 domain

UGT2B15: UDP Glycosyltransferase 2 Family, Polypeptide B15

VEGF: Vascular Endothelial Growth Factor

Many polypeptide mitogens, such as basic fibroblast growth factor (MIM 134920) and platelet-derived growth factors (MIM 173430, MIM 190040), are active on a wide range of different cell types. In contrast, vascular endothelial growth factor is a mitogen primarily for vascular endothelial cells. It is, however, structurally related to platelet-derived growth factor

WASL: Wiskott-Aldrich Syndrome-Like

The Wiskott-Aldrich syndrome (WAS) family of proteins share similar domain structure, and are involved in transduction of signals from receptors on the cell surface to the actin cytoskeleton. The presence of a number of different motifs suggests that they are regulated by a number of different stimuli, and interact with multiple proteins. Recent studies have demonstrated that these proteins, directly or indirectly, associate with the small GTPase, Cdc42, known to regulate formation of actin filaments, and the cytoskeletal organizing complex, Arp2/3. The WASL gene product is a homolog of WAS protein, however, unlike the latter, it is ubiquitously expressed and shows highest expression in neural tissues. It has been shown to bind Cdc42 directly, and induce formation of long actin microspikes.

CACNA2D2: Calcium Channel, Voltage-Dependent, Alpha 2/Delta Subunit 2

TFAP2B: Transcription Factor AP-2 Beta (Activating Enhancer Binding Protein 2 Beta)

TRIT1: tRNA Isopentenyltransferase 1

This enzyme modifies both cytoplasmic and mitochondrial tRNAs at A(37) to give isopentenyl A(37).

UGT2A1: UDP Glycosyltransferase 2 Family, Polypeptide A1

As PA SNPs are linked to other SNPs in neighboring genes on a chromosome (Linkage Disequilibrium) those SNPs could also be used as marker SNPs. In a recent publication it was shown that SNPs are linked over 100 kb in some cases more than 150 kb (Reich D. E. et al. Nature 411, 199-204, 2001). Hence SNPs lying in regions neighbouring PA SNPs could be linked to the latter and by this being a diagnostic marker. These associations could be performed as described for the gene polymorphism in methods.

Definitions

For convenience, the meaning of certain terms and phrases employed in the specification, examples, and appended claims are provided below. Moreover, the definitions by itself are intended to explain a further background of the invention.

The term “allele”, which is used interchangeably herein with “allelic variant” refers to alternative forms of a gene or portions thereof. Alleles occupy the same locus or position on homologous chromosomes. When a subject has two identical alleles of a gene, the subject is said to be homozygous for the gene or allele. When a subject has two different alleles of a gene, the subject is said to be heterozygous for the gene. Alleles of a specific gene can differ from each other in a single nucleotide, or several nucleotides, and can include substitutions, deletions, and insertions of nucleotides. An allele of a gene can also be a form of a gene containing a mutation.

The term “allelic variant of a polymorphic region of a gene” refers to a region of a gene having one of several nucleotide sequences found in that region of the gene in other individuals.

“Homology” or “identity” or “similarity” refers to sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing a position in each sequence which may be aligned for purposes of comparison. When a position in the compared sequence is occupied by the same base or amino acid, then the molecules are homologous at that position. A degree of homology between sequences is a function of the number of matching or homologous positions shared by the sequences. An “unrelated” or “non-homologous” sequence shares less than 40% identity, though preferably less than 25% identity, with one of the sequences of the present invention.

The term “a homologue of a nucleic acid” refers to a nucleic acid having a nucleotide sequence having a certain degree of homology with the nucleotide sequence of the nucleic acid or complement thereof. A homologue of a double stranded nucleic acid having SEQ ID NO. X is intended to include nucleic acids having a nucleotide sequence which has a certain degree of homology with SEQ ID NO. X or with the complement thereof. Preferred homologous of nucleic acids are capable of hybridizing to the nucleic acid or complement thereof.

The term “interact” as used herein is meant to include detectable interactions between molecules, such as can be detected using, for example, a hybridization assay.

The term interact is also meant to include “binding” interactions between molecules. Interactions may be, for example, protein-protein, protein-nucleic acid, protein-small molecule or small molecule-nucleic acid in nature.

The term “intronic sequence” or “intronic nucleotide sequence” refers to the nucleotide sequence of an intron or portion thereof.

The term “isolated” as used herein with respect to nucleic acids, such as DNA or RNA, refers to molecules separated from other DNAs or RNAs, respectively, that are present in the natural source of the macromolecule. The term isolated as used herein also refers to a nucleic acid or peptide that is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized.

Moreover, an “isolated nucleic acid” is meant to include nucleic acid fragments which are not naturally occurring as fragments and would not be found in the natural state. The term “isolated” is also used herein to refer to polypeptides which are isolated from other cellular proteins and is meant to encompass both purified and recombinant polypeptides.

The term “lipid” shall refer to a fat or fat-like substance that is insoluble in polar solvents such as water. The term “lipid” is intended to include true fats (e.g. esters of fatty acids and glycerol); lipids (phospholipids, cerebrosides, waxes); sterols (cholesterol, ergosterol) and lipoproteins (e.g. HDL, LDL and VLDL).

The term “locus” refers to a specific position in a chromosome. For example, a locus of a gene refers to the chromosomal position of the gene.

The term “modulation” as used herein refers to both up-regulation, (i.e., activation or stimulation), for example by agonizing, and down-regulation (i.e. inhibition or suppression), for example by antagonizing of a bioactivity (e.g. expression of a gene).

The term “molecular structure” of a gene or a portion thereof refers to the structure as defined by the nucleotide content (including deletions, substitutions, additions of one or more nucleotides), the nucleotide sequence, the state of methylation, and/or any other modification of the gene or portion thereof.

The term “mutated gene” refers to an allelic form of a gene, which is capable of altering the phenotype of a subject having the mutated gene relative to a subject which does not have the mutated gene. If a subject must be homozygous for this mutation to have an altered phenotype, the mutation is said to be recessive. If one copy of the mutated gene is sufficient to alter the genotype of the subject, the mutation is said to be dominant. If a subject has one copy of the mutated gene and has a phenotype that is intermediate between that of a homozygous and that of a heterozygous (for that gene) subject, the mutation is said to be co-dominant.

As used herein, the term “nucleic acid” refers to polynucleotides such as deoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid (RNA). The term should also be understood to include, as equivalents, derivatives, variants and analogs of either RNA or DNA made from nucleotide analogs, including peptide nucleic acids (PNA), morpholino oligonucleotides (J. Summerton and D. Weller, Antisense and Nucleic Acid Drug Development 7:187 (1997)) and, as applicable to the embodiment being described, single (sense or antisense) and double-stranded polynucleotides. Deoxyribonucleotides include deoxyadenosine, deoxycytidine, deoxyguanosine, and deoxythymidine. For purposes of clarity, when referring herein to a nucleotide of a nucleic acid, which can be DNA or an RNA, the term “adenosine”, “cytidine”, “guanosine”, and “thymidine” are used. It is understood that if the nucleic acid is RNA, a nucleotide having a uracil base is uridine.

The term “nucleotide sequence complementary to the nucleotide sequence set forth in SEQ ID NO. x” refers to the nucleotide sequence of the complementary strand of a nucleic acid strand having SEQ ID NO. x. The term “complementary strand” is used herein interchangeably with the term “complement”. The complement of a nucleic acid strand can be the complement of a coding strand or the complement of a non-coding strand. When referring to double stranded nucleic acids, the complement of a nucleic acid having SEQ ID NO. x refers to the complementary strand of the strand having SEQ ID NO. x or to any nucleic acid having the nucleotide sequence of the complementary strand of SEQ ID NO. x. When referring to a single stranded nucleic acid having the nucleotide sequence SEQ ID NO. x, the complement of this nucleic acid is a nucleic acid having a nucleotide sequence which is complementary to that of SEQ ID NO. x. The nucleotide sequences and complementary sequences thereof are always given in the 5′ to 3′ direction. The term “complement” and “reverse complement” are used interchangeably herein.

The term “operably linked” is intended to mean that the promoter is associated with the nucleic acid in such a manner as to facilitate transcription of the nucleic acid.

The term “polymorphism” refers to the coexistence of more than one form of a gene or portion thereof. A portion of a gene of which there are at least two different forms, i.e., two different nucleotide sequences, is referred to as a “polymorphic region of a gene”. A polymorphic region can be a single nucleotide, the identity of which differs in different alleles. A polymorphic region can also be several nucleotides long.

A “polymorphic gene” refers to a gene having at least one polymorphic region.

To describe a “polymorphic site” in a nucleotide sequence often there is used an “ambiguity code” that stands for the possible variations of nucleotides in one site. The list of ambiguity codes is summarized in the following table:

Ambiguity Codes (IUPAC
Nomenclature)
Bc/g/t
Da/g/t
Ha/c/t
Kg/t
Ma/c
Na/c/g/t
Ra/g
Sc/g
Va/c/g
Wa/t
Yc/t

So, for example, a “R” in a nucleotide sequence means that either an “a” or a “g” could be at that position.

The terms “protein”, “polypeptide” and “peptide” are used interchangeably herein when referring to a gene product.

A “regulatory element”, also termed herein “regulatory sequence is intended to include elements which are capable of modulating transcription from a basic promoter and include elements such as enhancers and silencers. The term “enhancer”, also referred to herein as “enhancer element”, is intended to include regulatory elements capable of increasing, stimulating, or enhancing transcription from a basic promoter. The term “silencer”, also referred to herein as “silencer element” is intended to include regulatory elements capable of decreasing, inhibiting, or repressing transcription from a basic promoter. Regulatory elements are typically present in 5′ flanking regions of genes. However, regulatory elements have also been shown to be present in other regions of a gene, in particular in introns. Thus, it is possible that genes have regulatory elements located in introns, exons, coding regions, and 3′ flanking sequences. Such regulatory elements are also intended to be encompassed by the present invention and can be identified by any of the assays that can be used to identify regulatory elements in 5′ flanking regions of genes.

The term “regulatory element” further encompasses “tissue specific” regulatory elements, i.e., regulatory elements which effect expression of the selected DNA sequence preferentially in specific cells (e.g., cells of a specific tissue). gene expression occurs preferentially in a specific cell if expression in this cell type is significantly higher than expression in other cell types. The term “regulatory element” also encompasses non-tissue specific regulatory elements, i.e., regulatory elements which are active in most cell types. Furthermore, a regulatory element can be a constitutive regulatory element, i.e., a regulatory element which constitutively regulates transcription, as opposed to a regulatory element which is inducible, i.e., a regulatory element which is active primarily in response to a stimulus. A stimulus can be, e.g., a molecule, such as a hormone, cytokine, heavy metal, phorbol ester, cyclic AMP (cAMP), or retinoic acid.

Regulatory elements are typically bound by proteins, e.g., transcription factors. The term “transcription factor” is intended to include proteins or modified forms thereof, which interact preferentially with specific nucleic acid sequences, i.e., regulatory elements, and which in appropriate conditions stimulate or repress transcription. Some transcription factors are active when they are in the form of a monomer. Alternatively, other transcription factors are active in the form of a dimer consisting of two identical proteins or different proteins (heterodimer). Modified forms of transcription factors are intended to refer to transcription factors having a post-translational modification, such as the attachment of a phosphate group. The activity of a transcription factor is frequently modulated by a post-translational modification. For example, certain transcription factors are active only if they are phosphorylated on specific residues. Alternatively, transcription factors can be active in the absence of phosphorylated residues and become inactivated by phosphorylation. A list of known transcription factors and their DNA binding site can be found, e.g., in public databases, e.g., TFMATRIX Transcription Factor Binding Site Profile database.

As used herein, the term “specifically hybridizes” or “specifically detects” refers to the ability of a nucleic acid molecule of the invention to hybridize to at least approximately 6, 12, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130 or 140 consecutive nucleotides of either strand of a gene.

The term “wild-type allele” refers to an allele of a gene which, when present in two copies in a subject results in a wild-type phenotype. There can be several different wild-type alleles of a specific gene, since certain nucleotide changes in a gene may not affect the phenotype of a subject having two copies of the gene with the nucleotide changes.

“Adverse drug reaction” (ADR) as used herein refers to an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which

predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product. In it's most severe form an ADR might lead to the death of an individual.

The term “Drug Response” is intended to mean any response that a patient exhibits upon drug administration. Specifically drug response includes beneficial, i.e. desired drug effects, ADR or no detectable reaction at all. More specifically the term drug response could also have a qualitative meaning, i.e. it embraces low or high beneficial effects, respectively and mild or severe ADR, respectively. The term “Statin Response” as used herein refers to drug response after statin administration. An individual drug response includes also a good or bad metabolizing of the drug, meaning that “bad metabolizers” accumulate the drug in the body and by this could show side effects of the drug due to accumulative overdoses.

“Candidate gene” as used herein includes genes that can be assigned to either normal cardiovascular function or to metabolic pathways that are related to onset and/or progression of cardiovascular diseases.

With regard to drug response the term “candidate gene” includes genes that can be assigned to distinct phenotypes regarding the patient's response to drug administration. Those phenotypes may include patients who benefit from relatively small amounts of a given drug (high responders) or patients who need relatively high doses in order to obtain the same benefit (low responders). In addition those phenotypes may include patients who can tolerate high doses of a medicament without exhibiting ADR, or patients who suffer from ADR even after receiving only low doses of a medicament.

As neither the development of cardiovascular diseases nor the patient's response to drug administration is completely understood, the term “candidate gene” may also comprise genes with presently unknown function.

“PA SNP” (phenotype associated SNP) refers to a polymorphic site which shows a significant association with a patients phenotype (healthy, diseased, low or high responder, drug tolerant, ADR prone, etc.)

“PA gene” (phenotype associated gene) refers to a genomic locus harbouring a PA SNP, irrespective of the actual function of this gene locus.

PA gene polypeptide refers to a polypeptide encoded at least in part by a PA gene.

The term “Secondary SNP” is intended to mean a SNP that is in neighborhood to at least one other (“primary”) SNP. Due to linkage disequilibrium both primary and secondary SNP(s) might shown a similar association with a phenotype.

The term “Haplotype” as used herein refers to a group of two or more SNPs that are functionally and/or spatially linked. I.e. haplotypes define groups of SNPs that lie inside genes belonging to identical (or related metabolic) pathways and/or lie on the same chromosome. Haplotypes are expected to give better predictive/diagnostic information than a single SNP

The term “statin” is intended to embrace all inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Statins specifically inhibit the enzyme HMG-CoA reductase which catalyzes the rate limiting step in cholesterol biosynthesis. Known statins are Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Pravastatin and Simvastatin.

Methods for Assessing Cardiovascular Status

The present invention provides diagnostic methods for assessing cardiovascular status in a human individual. Cardiovascular status as used herein refers to the physiological status of an individual's cardiovascular system as reflected in one or more markers or indicators. Status markers include without limitation clinical measurements such as, e.g., blood pressure, electrocardiographic profile, and differentiated blood flow analysis as well as measurements of LDL- and HDL-Cholesterol levels, other lipids and other well established clinical parameters that are standard in the art. Status markers according to the invention include diagnoses of one or more cardiovascular syndromes, such as, e.g., hypertension, acute myocardial infarction, silent myocardial infarction, stroke, and atherosclerosis. It will be understood that a diagnosis of a cardiovascular syndrome made by a medical practitioner encompasses clinical measurements and medical judgement. Status markers according to the invention are assessed using conventional methods well known in the art. Also included in the evaluation of cardiovascular status are quantitative or qualitative changes in status markers with time, such as would be used, e.g., in the determination of an individual's response to a particular therapeutic regimen.

The methods are carried out by the steps of:

(i) determining the sequence of one or more polymorphic positions within one, several or all of the genes listed in Examples or other genes mentioned in this file in the individual to establish a polymorphic pattern for the individual; and

(ii) comparing the polymorphic pattern established in (i) with the polymorphic patterns of humans exhibiting different markers of cardiovascular status. The polymorphic pattern of the individual is, preferably, highly similar and, most preferably, identical to the poly-morphic pattern of individuals who exhibit particular status markers, cardiovascular syndromes, and/or particular patterns of response to therapeutic interventions. Poly-morphic patterns may also include polymorphic positions in other genes which are shown, in combination with one or more polymorphic positions in the genes listed in the Examples, to correlate with the presence of particular status markers. In one embodiment, the method involves comparing an individual's polymorphic pattern with polymorphic patterns of individuals who have been shown to respond positively or negatively to a particular therapeutic regimen. Therapeutic regimen as used herein refers to treatments aimed at the elimination or amelioration of symptoms and events associated cardiovascular disease. Such treatments include without limitation one or more of alteration in diet, lifestyle, and exercise regimen; invasive and noninvasive surgical techniques such as atherectomy, angioplasty, and coronary bypass surgery; and pharmaceutical interventions, such as administration of ACE inhibitors, angiotensin II receptor antagonists, diuretics, alpha-adrenoreceptor antagonists, cardiac glycosides, phosphodiesterase inhibitors, beta-adrenoreceptor antagonists, calcium channel blockers, HMG-CoA reductase inhibitors, imidazoline receptor blockers, endothelin receptor blockers, organic nitrites, and modulators of protein function of genes listed in the Examples. Interventions with pharmaceutical agents not yet known whose activity correlates with particular polymorphic patterns associated with cardiovascular disease are also encompassed. It is contemplated, for example, that patients who are candidates for a particular therapeutic regimen will be screened for polymorphic patterns that correlate with responsivity to that particular regimen.

In a preferred embodiment, the method involves comparing an individual's polymorphic pattern with polymorphic patterns of individuals who exhibit or have exhibited one or more markers of cardiovascular disease, such as, e.g., elevated LDL-Cholesterol levels, high blood pressure, abnormal electrocardiographic profile, myocardial infarction, stroke, or atherosclerosis.

In another embodiment, the method involves comparing an individual's polymorphic pattern with polymorphic patterns of individuals who exhibit or have exhibited one or more drug related phenotypes, such as, e.g., low or high drug response, or adverse drug reactions.

In practicing the methods of the invention, an individual's polymorphic pattern can be established by obtaining DNA from the individual and determining the sequence at predetermined polymorphic positions in the genes such as those described in this file.

The DNA may be obtained from any cell source. Non-limiting examples of cell sources available in clinical practice include blood cells, buccal cells, cervicovaginal cells, epithelial cells from urine, fetal cells, or any cells present in tissue obtained by biopsy. Cells may also be obtained from body fluids, including without limitation blood, saliva, sweat, urine, cerebrospinal fluid, feces, and tissue exudates at the site of infection or inflammation. DNA is extracted from the cell source or body fluid using any of the numerous methods that are standard in the art. It will be understood that the particular method used to extract DNA will depend on the nature of the source.

Diagnostic and Prognostic Assays

The present invention provides methods for determining the molecular structure of at least one polymorphic region of a gene, specific allelic variants of said polymorphic region being associated with cardiovascular disease. In one embodiment, determining the molecular structure of a polymorphic region of a gene comprises determining the identity of the allelic variant. A polymorphic region of a gene, of which specific alleles are associated with cardiovascular disease can be located in an exon, an intron, at an intron/exon border, or in the promoter of the gene.

The invention provides methods for determining whether a subject has, or is at risk, of developing a cardiovascular disease. Such disorders can be associated with an aberrant gene activity, e.g., abnormal binding to a form of a lipid, or an aberrant gene protein level. An aberrant gene protein level can result from an aberrant transcription or post-transcriptional regulation. Thus, allelic differences in specific regions of a gene can result in differences of gene protein due to differences in regulation of expression. In particular, some of the identified polymorphisms in the human gene may be associated with differences in the level of transcription, RNA maturation, splicing, or translation of the gene or transcription product.

In preferred embodiments, the methods of the invention can be characterized as comprising detecting, in a sample of cells from the subject, the presence or absence of a specific allelic variant of one or more polymorphic regions of a gene. The allelic differences can be: (i) a difference in the identity of at least one nucleotide or (ii) a difference in the number of nucleotides, which difference can be a single nucleotide or several nucleotides.

A preferred detection method is allele specific hybridization using probes overlapping the polymorphic site and having about 5, 10, 20, 25, or 30 nucleotides around the polymorphic region. Examples of probes for detecting specific allelic variants of the polymorphic region located in intron X are probes comprising a nucleotide sequence set forth in any of SEQ ID NO. X. In a preferred embodiment of the invention, several probes capable of hybridizing specifically to allelic variants are attached to a solid phase support, e.g., a “chip”. Oligonucleotides can be bound to a solid support by a variety of processes, including lithography. For example a chip can hold up to 250,000 oligonucleotides (GeneChip, Affymetrix). Mutation detection analysis using these chips comprising oligonucleotides, also termed “DNA probe arrays” is described e.g., in Cronin et al. (1996) Human Mutation 7:244 and in Kozal et al. (1996) Nature Medicine 2:753. In one embodiment, a chip comprises all the allelic variants of at least one polymorphic region of a gene. The solid phase support is then contacted with a test nucleic acid and hybridization to the specific probes is detected. Accordingly, the identity of numerous allelic variants of one or more genes can be identified in a simple hybridization experiment. For example, the identity of the allelic variant of the nucleotide polymorphism of nucleotide A or G at position 33 of Seq ID 1 (baySNP179) and that of other possible polymorphic regions can be determined in a single hybridization experiment.

In other detection methods, it is necessary to first amplify at least a portion of a gene prior to identifying the allelic variant. Amplification can be performed, e.g., by PCR and/or LCR, according to methods known in the art. In one embodiment, genomic DNA of a cell is exposed to two PCR primers and amplification for a number of cycles sufficient to produce the required amount of amplified DNA. In preferred embodiments, the primers are located between 40 and 350 base pairs apart. Preferred primers for amplifying gene fragments of genes of this file are listed in Table 2 in the Examples.

Alternative amplification methods include: self sustained sequence replication (Guatelli, J. C. et al., 1990, Proc. Natl. Acad. Sci. U.S.A. 87:1874-1878), transcriptional amplification system (Kwoh, D. Y. et al., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:1173-1177), Q-Beta Replicase (Lizardi, P. M. et al., 1988, Bio/Technology 6:1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers.

In one embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence at least a portion of a gene and detect allelic variants, e.g., mutations, by comparing the sequence of the sample sequence with the corresponding wild-type (control) sequence. Exemplary sequencing reactions include those based on techniques developed by Maxam and Gilbert (Proc. Natl. Acad Sci USA (1977) 74:560) or Sanger (Sanger et al (1977) Proc. Nat. Acad. Sci 74:5463). It is also contemplated that any of a variety of automated sequencing procedures may be utilized when performing the subject assays (Biotechniques (1995) 19:448), including sequencing by mass spectrometry (see, for example, U.S. Pat. No. 5,547,835 and international patent application Publication Number WO 94/16101, entitled DNA Sequencing by Mass Spectrometry by H. Koster; U.S. Pat. No. 5,547,835 and international patent application Publication Number WO 94/21822 entitled “DNA Sequencing by Mass Spectrometry Via Exonuclease Degradation” by H. Koster), and U.S. Pat. No. 5,605,798 and International Patent Application No. PCT/US96/03651 entitled DNA Diagnostics Based on Mass Spectrometry by H. Koster; Cohen et al. (1996) Adv Chromatogr 36:127-162; and Griffin et al. (1993) Appl Biochem Biotechnol 38:147-159). It will be evident to one skilled in the art that, for certain embodiments, the occurrence of only one, two or three of the nucleic acid bases need be determined in the sequencing reaction. For instance, A-track or the like, e.g., where only one nucleotide is detected, can be carried out.

Yet other sequencing methods are disclosed, e.g., in U.S. Pat. No. 5,580,732 entitled “Method of DNA sequencing employing a mixed DNA-polymer chain probe” and U.S. Pat. No. 5,571,676 entitled “Method for mismatch-directed in vitro DNA sequencing”.

In some cases, the presence of a specific allele of a gene in DNA from a subject can be shown by restriction enzyme analysis. For example, a specific nucleotide polymorphism can result in a nucleotide sequence comprising a restriction site which is absent from the nucleotide sequence of another allelic variant.

In other embodiments, alterations in electrophoretic mobility is used to identify the type of gene allelic variant. For example, single strand conformation polymorphism (SSCP) may be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids (Orita et al. (1989) Proc Natl. Acad. Sci USA 86:2766, see also Cotton (1993) Mutat Res 285:125-144; and Hayashi (1992) Genet Anal Tech Appl 9:73-79). Single-stranded DNA fragments of sample and control nucleic acids are denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity of the assay may be enhanced by using PNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In another preferred embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility (Keen et al. (1991) Trends Genet 7:5).

In yet another embodiment, the identity of an allelic variant of a polymorphic region is obtained by analyzing the movement of a nucleic acid comprising the polymorphic region in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE) (Myers et al (1985) Nature 313:495). When DGGE is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place of a denaturing agent gradient to identify differences in the mobility of control and sample DNA (Rosenbaum and Reissner (1987) Biophys Chem 265:1275).

Examples of techniques for detecting differences of at least one nucleotide between 2 nucleic acids include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide probes may be prepared in which the known polymorphic nucleotide is placed centrally (allele-specific probes) and then hybridized to target DNA under conditions which permit hybridization only if a perfect match is found (Saiki et al. (1986) Nature 324:163); Saiki et al (1989) Proc. Natl. Acad. Sci USA 86:6230; and Wallace et al. (1979) Nucl. Acids Res. 6:3543). Such allele specific oligonucleotide hybridization techniques may be used for the simultaneous detection of several nucleotide changes in different polymorphic regions of gene. For example, oligonucleotides having nucleotide sequences of specific allelic variants are attached to a hybridizing membrane and this membrane is then hybridized with labeled sample nucleic acid. Analysis of the hybridization signal will then reveal the identity of the nucleotides of the sample nucleic acid.

Alternatively, allele specific amplification technology which depends on selective PCR amplification may be used. Oligonucleotides used as primers for specific amplification may carry the allelic variant of interest in the center of the molecule (so that amplification depends on differential hybridization) (Gibbs et al (1989) Nucleic Acids Res. 17:2437-2448) or at the extreme 3′ end of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (Prossner (1993) Tibtech 11:238; Newton et al. (1989) Nucl. Acids Res. 17:2503). This technique is also termed “PROBE” for Probe Oligo Base Extension. In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection (Gasparini et al (1992) Mol. Cell Probes 6:1).

In another embodiment, identification of the allelic variant is carried out using an oligonucleotide ligation assay (OLA), as described, e.g., in U.S. Pat. No. 4,998,617 and in Landegren, U. et al., Science 241:1077-1080 (1988). The OLA protocol uses two oligonucleotides which are designed to be capable of hybridizing to abutting sequences of a single strand of a target. One of the oligonucleotides is linked to a separation marker, e.g., biotinylated, and the other is detectably labeled. If the precise complementary sequence is found in a target molecule, the oligonucleotides will hybridize such that their termini abut, and create a ligation substrate. Ligation then permits the labeled oligonucleotide to be recovered using avidin, or another biotin ligand. Nickerson, D. A. et al. have described a nucleic acid detection assay that combines attributes of PCR and OLA (Nickerson, D. A. et al., Proc. Natl. Acad. Sci. (U.S.A.) 87:8923-8927 (1990). In this method, PCR is used to achieve the exponential amplification of target DNA, which is then detected using OLA.

Several techniques based on this OLA method have been developed and can be used to detect specific allelic variants of a polymorphic region of a gene. For example, U.S. Pat. No. 5,593,826 discloses an OLA using an oligonucleotide having 3′-amino group and a 5′-phosphorylated oligonucleotide to form a conjugate having a phosphoramidate linkage. In another variation of OLA described in Tobe et al. ((1996) Nucleic Acids Res 24: 3728), OLA combined with PCR permits typing of two alleles in a single microtiter well. By marling each of the allele-specific primers with a unique hapten, i.e. digoxigenin and fluorescein, each LA reaction can be detected by using hapten specific antibodies that are labeled with different enzyme reporters, alkaline phosphatase or horseradish peroxidase. This system permits the detection of the two alleles using a high throughput format that leads to the production of two different colors.

The invention further provides methods for detecting single nucleotide polymorphisms in a gene. Because single nucleotide polymorphisms constitute sites of variation flanked by regions of invariant sequence, their analysis requires no more than the determination of the identity of the single nucleotide present at the site of variation and it is unnecessary to determine a complete gene sequence for each patient. Several methods have been developed to facilitate the analysis of such single nucleotide polymorphisms.

In one embodiment, the single base polymorphism can be detected by using a specialized exonuclease-resistant nucleotide, as disclosed, e.g., in Mundy, C. R. (U.S. Pat. No. 4,656,127). According to the method, a primer complementary to the allelic sequence immediately 3′ to the polymorphic site is permitted to hybridize to a target molecule obtained from a particular animal or human. If the polymorphic site on the target molecule contains a nucleotide that is complementary to the particular exonuclease-resistant nucleotide derivative present, then that derivative will be incorporated onto the end of the hybridized primer. Such incorporation renders the primer resistant to exonuclease, and thereby permits its detection. Since the identity of the exonuclease-resistant derivative of the sample is known, a finding that the primer has become resistant to exonucleases reveals that the nucleotide present in the polymorphic site of the target molecule was complementary to that of the nucleotide derivative used in the reaction. This method has the advantage that it does not require the determination of large amounts of extraneous sequence data.

In another embodiment of the invention, a solution-based method is used for determining the identity of the nucleotide of a polymorphic site. Cohen, D. et al. (French Patent 2,650,840; PCT Appln. No. WO91/02087). As in the Mundy method of U.S. Pat. No. 4,656,127, a primer is employed that is complementary to allelic sequences immediately 3′ to a polymorphic site. The method determines the identity of the nucleotide of that site using labeled dideoxynucleotide derivatives, which, if complementary to the nucleotide of the polymorphic site will become incorporated onto the terminus of the primer.

An alternative method, known as Genetic Bit Analysis or GBA TM is described by Goelet, P. et al. (PCT Appln. No. 92/15712). The method of Goelet, P. et al. uses mixtures of labeled terminators and a primer that is complementary to the sequence 3′ to a polymorphic site. The labeled terminator that is incorporated is thus determined by, and complementary to, the nucleotide present in the polymorphic site of the target molecule being evaluated. In contrast to the method of Cohen et al. (French Patent 2,650,840; PCT Appln. No. WO91/02087) the method of Goelet, P. et al. is preferably a heterogeneous phase assay, in which the primer or the target molecule is immobilized to a solid phase.

Recently, several primer-guided nucleotide incorporation procedures for assaying polymorphic sites in DNA have been described (Komher, J. S. et al., Nucl. Acids. Res. 17:7779-7784 (1989); Sokolov, B. P., Nucl. Acids Res. 18:3671 (1990); Syvanen, A.-C., et al., Genomics 8:684-692 (1990), Kuppuswamy, M. N. et al., Proc. Natl. Acad. Sci. (U.S.A.) 88:1143-1147 (1991); Prezant, T. R. et al., Hum. Mutat. 1:159-164 (1992); Ugozzoli, L. et al., GATA 9:107-112 (1992); Nyren, P. et al., Anal. Biochem. 208:171-175 (1993)). These methods differ from GBA TM in that they all rely on the incorporation of labeled deoxynucleotides to discriminate between bases at a polymorphic site. In such a format, since the signal is proportional to the number of deoxynucleotides incorporated, polymorphisms that occur in runs of the same nucleotide can result in signals that are proportional to the length of the run (Syvanen, A.-C., et al., Amer. J. Hum. Genet. 52:46-59 (1993)).

For determining the identity of the allelic variant of a polymorphic region located in the coding region of a gene, yet other methods than those described above can be used. For example, identification of an allelic variant which encodes a mutated gene protein can be performed by using an antibody specifically recognizing the mutant protein in, e.g., immunohistochemistry or immunoprecipitation. Antibodies to wild-type gene protein are described, e.g., in Acton et al. (1999) Science 271:518 (anti-mouse gene antibody cross-reactive with human gene). Other antibodies to wild-type gene or mutated forms of gene proteins can be prepared according to methods known in the art. Alternatively, one can also measure an activity of an gene protein, such as binding to a lipid or lipoprotein. Binding assays are known in the art and involve, e.g., obtaining cells from a subject, and performing binding experiments with a labeled lipid, to determine whether binding to the mutated form of the receptor differs from binding to the wild-type of the receptor.

If a polymorphic region is located in an exon, either in a coding or non-coding region of the gene, the identity of the allelic variant can be determined by determining the molecular structure of the mRNA, pre-mRNA, or cDNA. The molecular structure can be determined using any of the above described methods for determining the molecular structure of the genomic DNA, e.g., sequencing and SSCP.

The methods described herein may be performed, for example, by utilizing pre-packaged diagnostic kits, such as those described above, comprising at least one probe or primer nucleic acid described herein, which may be conveniently used, e.g., to determine whether a subject has or is at risk of developing a disease associated with a specific gene allelic variant.

Sample nucleic acid for using in the above-described diagnostic and prognostic methods can be obtained from any cell type or tissue of a subject. For example, a subject's bodily fluid (e.g. blood) can be obtained by known techniques (e.g. venipuncture) or from human tissues like heart (biopsies, transplanted organs). Alternatively, nucleic acid tests can be performed on dry samples (e.g. hair or skin). Fetal nucleic acid samples for prenatal diagnostics can be obtained from maternal blood as described in International Patent Application No. WO91/07660 to Bianchi. Alternatively, amniocytes or chorionic villi may be obtained for performing prenatal testing.

Diagnostic procedures may also be performed in situ directly upon tissue sections (fixed and/or frozen) of patient tissue obtained from biopsies or resections, such that no nucleic acid purification is necessary. Nucleic acid reagents may be used as probes and/or primers for such in situ procedures (see, for example, Nuovo, G. J., 1992, PCR in situ hybridization: protocols and applications, Raven Press, New York).

In addition to methods which focus primarily on the detection of one nucleic acid sequence, profiles may also be assessed in such detection schemes. Fingerprint profiles may be generated, for example, by utilizing a differential display procedure, Northern analysis and/or RT-PCR.

In practicing the present invention, the distribution of polymorphic patterns in a large number of individuals exhibiting particular markers of cardiovascular status or drug response is determined by any of the methods described above, and compared with the distribution of polymorphic patterns in patients that have been matched for age, ethnic origin, and/or any other statistically or medically relevant parameters, who exhibit quantitatively or qualitatively different status markers. Correlations are achieved using any method known in the art, including nominal logistic regression, chi square tests or standard least squares regression analysis. In this manner, it is possible to establish statistically significant correlations between particular polymorphic patterns and particular cardiovascular statuses (given in p values). It is further possible to establish statistically significant correlations between particular polymorphic patterns and changes in cardiovascular status or drug response such as, would result, e.g., from particular treatment regimens. In this manner, it is possible to correlate polymorphic patterns with responsivity to particular treatments.

In another embodiment of the present invention two or more polymorphic regions are combined to define so called ‘haplotypes’. Haplotypes are groups of two or more SNPs that are functionally and/or spatially linked. It is possible to combine SNPs that are disclosed in the present invention either with each other or with additional polymorphic regions to form a haplotype. Haplotypes are expected to give better predictive/diagnostic information than a single SNP.

In a preferred embodiment of the present invention a panel of SNPs/haplotypes is defined that predicts the risk for CVD or drug response. This predictive panel is then used for genotyping of patients on a platform that can genotype multiple SNPs at the same time (Multiplexing). Preferred platforms are e.g. gene chips (Affymetrix) or the Luminex LabMAP reader. The subsequent identification and evaluation of a patient's haplotype can then help to guide specific and individualized therapy.

For example the present invention can identify patients exhibiting genetic polymorphisms or haplotypes which indicate an increased risk for adverse drug reactions. In that case the drug dose should be lowered in a way that the risk for ADR is diminished. Also if the patient's response to drug administration is particularly high (or the patient is badly metabolizing the drug), the drug dose should be lowered to avoid the risk of ADR.

In turn if the patient's response to drug administration is low (or the patient is a particularly high metabolizer of the drug), and there is no evident risk of ADR, the drug dose should be raised to an efficacious level.

It is self evident that the ability to predict a patient's individual drug response should affect the formulation of a drug, i.e. drug formulations should be tailored in a way that they suit the different patient classes (low/high responder, poor/good metabolizer, ADR prone patients). Those different drug formulations may encompass different doses of the drug, i.e. the medicinal products contains low or high amounts of the active substance. In another embodiment of the invention the drug formulation may contain additional substances that facilitate the beneficial effects and/or diminish the risk for ADR (Folkers et al. 1991, U.S. Pat. No. 5,316,765).

Isolated Polymorphic Nucleic Acids, Probes, and Vectors

The present invention provides isolated nucleic acids comprising the polymorphic positions described herein for human genes; vectors comprising the nucleic acids; and transformed host cells comprising the vectors. The invention also provides probes which are useful for detecting these polymorphisms.

In practicing the present invention, many conventional techniques in molecular biology, microbiology, and recombinant DNA, are used. Such techniques are well known and are explained fully in, for example, Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; DNA Cloning: A Practical Approach, Volumes I and II, 1985 (D. N. Glover ed.); Oligonucleotide Synthesis, 1984, (M. L. Gait ed.); Nucleic Acid Hybridization, 1985, (Hames and Higgins); Ausubel et al., Current Protocols in Molecular Biology, 1997, (John Wiley and Sons); and Methods in Enzymology Vol. 154 and Vol. 155 (Wu and Grossman, and Wu, eds., respectively).

Insertion of nucleic acids (typically DNAs) comprising the sequences in a functional surrounding like full length cDNA of the present invention into a vector is easily accomplished when the termini of both the DNAs and the vector comprise compatible restriction sites. If this cannot be done, it may be necessary to modify the termini of the DNAs and/or vector by digesting back single-stranded DNA overhangs generated by restriction endonuclease cleavage to produce blunt ends, or to achieve the same result by filling in the single-stranded termini with an appropriate DNA polymerase.

Alternatively, any site desired may be produced, e.g., by ligating nucleotide sequences (linkers) onto the termini. Such linkers may comprise specific oligonucleotide sequences that define desired restriction sites. Restriction sites can also be generated by the use of the polymerase chain reaction (PCR). See, e.g., Saiki et al., 1988, Science 239:48. The cleaved vector and the DNA fragments may also be modified if required by homopolymeric tailing.

The nucleic acids may be isolated directly from cells or may be chemically synthesized using known methods. Alternatively, the polymerase chain reaction (PCR) method can be used to produce the nucleic acids of the invention, using either chemically synthesized strands or genomic material as templates. Primers used for PCR can be synthesized using the sequence information provided herein and can further be designed to introduce appropriate new restriction sites, if desirable, to facilitate incorporation into a given vector for recombinant expression.

The nucleic acids of the present invention may be flanked by native gene sequences, or may be associated with heterologous sequences, including promoters, enhancers, response elements, signal sequences, polyadenylation sequences, introns, 5′- and 3′-noncoding regions, and the like. The nucleic acids may also be modified by many means known in the art. Non-limiting examples of such modifications include methylation, “caps”, substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoroamidates, carbamates, morpholines etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.). Nucleic acids may contain one or more additional covalently linked moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), intercalators (e.g., acridine, psoralen, etc.), chelators (e.g., metals, radioactive metals, iron, oxidative metals, etc.), and alkylators. PNAs are also included. The nucleic acid may be derivatized by formation of a methyl or ethyl phosphotriester or an alkyl phosphoramidate linkage. Furthermore, the nucleic acid sequences of the present invention may also be modified with a label capable of providing a detectable signal, either directly or indirectly. Exemplary labels include radioisotopes, fluorescent molecules, biotin, and the like.

The invention also provides nucleic acid vectors comprising the gene sequences or derivatives or fragments thereof of genes described in the Examples. A large number of vectors, including plasmid and fungal vectors, have been described for replication and/or expression in a variety of eukaryotic and prokaryotic hosts, and may be used for gene therapy as well as for simple cloning or protein expression. Non-limiting examples of suitable vectors include without limitation pUC plasmids, pET plasmids (Novagen, Inc., Madison, Wis.), or pRSET or pREP (Invitrogen, San Diego, Calif.), and many appropriate host cells, using methods disclosed or cited herein or otherwise known to those skilled in the relevant art. The particular choice of vector/host is not critical to the practice of the invention.

Suitable host cells may be transformed/transfected/infected as appropriate by any suitable method including electroporation, CaCl2 mediated DNA uptake, fungal or viral infection, microinjection, microprojectile, or other established methods. Appropriate host cells included bacteria, archebacteria, fungi, especially yeast, and plant and animal cells, especially mammalian cells. A large number of transcription initiation and termination regulatory regions have been isolated and shown to be effective in the transcription and translation of heterologous proteins in the various hosts. Examples of these regions, methods of isolation, manner of manipulation, etc. are known in the art. Under appropriate expression conditions, host cells can be used as a source of recombinantly produced peptides and polypeptides encoded by genes of the Examples. Nucleic acids encoding peptides or polypeptides from gene sequences of the Examples may also be introduced into cells by recombination events. For example, such a sequence can be introduced into a cell and thereby effect homologous recombination at the site of an endogenous gene or a sequence with substantial identity to the gene. Other recombination-based methods such as non-homologous recombinations or deletion of endogenous genes by homologous recombination may also be used.

In case of proteins that form heterodimers or other multimers, both or all subunits have to be expressed in one system or cell.

The nucleic acids of the present invention find use as probes for the detection of genetic polymorphisms and as templates for the recombinant production of normal or variant peptides or polypeptides encoded by genes listed in the Examples.

Probes in accordance with the present invention comprise without limitation isolated nucleic acids of about 10-100 bp, preferably 15-75 bp and most preferably 17-25 bp in length, which hybridize at high stringency to one or more of the polymorphic sequences disclosed herein or to a sequence immediately adjacent to a polymorphic position. Furthermore, in some embodiments a full-length gene sequence may be used as a probe. In one series of embodiments, the probes span the polymorphic positions in genes disclosed herein. In another series of embodiments, the probes correspond to sequences immediately adjacent to the polymorphic positions.

Polymorphic Polypeptides and Polymorphism-Specific Antibodies

The present invention encompasses isolated peptides and polypeptides encoded by genes listed in the Examples comprising polymorphic positions disclosed herein. In one preferred embodiment, the peptides and polypeptides are useful screening targets to identify cardiovascular drugs. In another preferred embodiments, the peptides and polypeptides are capable of eliciting antibodies in a suitable host animal that react specifically with a polypeptide comprising the polymorphic position and distinguish it from other polypeptides having a different sequence at that position.

Polypeptides according to the invention are preferably at least five or more residues in length, preferably at least fifteen residues. Methods for obtaining these polypeptides are described below. Many conventional techniques in protein biochemistry and immunology are used. Such techniques are well known and are explained in Immunochemical Methods in Cell and Molecular Biology, 1987 (Mayer and Waler, eds; Academic Press, London); Scopes, 1987, Protein Purification: Principles and Practice, Second Edition (Springer-Verlag, N.Y.) and Handbook of Experimental immunology, 1986, Volumes I-IV (Weir and Blackwell eds.).

Nucleic acids comprising protein-coding sequences can be used to direct the ITT recombinant expression of polypeptides encoded by genes disclosed herein in intact cells or in cell-free translation systems. The known genetic code, tailored if desired for more efficient expression in a given host organism, can be used to synthesize oligonucleotides encoding the desired amino acid sequences. The polypeptides may be isolated from human cells, or from heterologous organisms or cells (including, but not limited to, bacteria, fungi, insect, plant, and mammalian cells) into which an appropriate protein-coding sequence has been introduced and expressed. Furthermore, the polypeptides may be part of recombinant fusion proteins.

Peptides and polypeptides may be chemically synthesized by commercially available automated procedures, including, without limitation, exclusive solid phase synthesis, partial solid phase methods, fragment condensation or classical solution synthesis. The polypeptides are preferably prepared by solid phase peptide synthesis as described by Merrifield, 1963, J. Am. Chem. Soc. 85:2149.

Methods for polypeptide purification are well-known in the art, including, without limitation, preparative disc-gel electrophoresis, isoelectric focusing, HPLC, reversed-phase HPLC, gel filtration, ion exchange and partition chromatography, and countercurrent distribution. For some purposes, it is preferable to produce the polypeptide in a recombinant system in which the protein contains an additional sequence tag that facilitates purification, such as, but not limited to, a polyhistidine sequence. The polypeptide can then be purified from a crude lysate of the host cell by chromatography on an appropriate solid-phase matrix. Alternatively, antibodies produced against peptides encoded by genes disclosed herein, can be used as purification reagents. Other purification methods are possible.

The present invention also encompasses derivatives and homologues of the polypeptides. For some purposes, nucleic acid sequences encoding the peptides may be altered by substitutions, additions, or deletions that provide for functionally equivalent molecules, i.e., function-conservative variants. For example, one or more amino acid residues within the sequence can be substituted by another amino acid of similar properties, such as, for example, positively charged amino acids (arginine, lysine, and histidine); negatively charged amino acids (aspartate and glutamate); polar neutral amino acids; and non-polar amino acids.

The isolated polypeptides may be modified by, for example, phosphorylation, sulfation, acylation, or other protein modifications. They may also be modified with a label capable of providing a detectable signal, either directly or indirectly, including, but not limited to, radioisotopes and fluorescent compounds.

The present invention also encompasses antibodies that specifically recognize the polymorphic positions of the invention and distinguish a peptide or polypeptide containing a particular polymorphism from one that contains a different sequence at that position. Such polymorphic position-specific antibodies according to the present invention include polyclonal and monoclonal antibodies. The antibodies may be elicited in an animal host by immunization with peptides encoded by genes disclosed herein or may be formed by in vitro immunization of immune cells. The immunogenic components used to elicit the antibodies may be isolated from human cells or produced in recombinant systems. The antibodies may also be produced in recombinant systems programmed with appropriate antibody-encoding DNA. Alternatively, the antibodies may be constructed by biochemical reconstitution of purified heavy and light chains. The antibodies include hybrid antibodies (i.e., containing two sets of heavy chain/light chain combinations, each of which recognizes a different antigen), chimeric antibodies (i.e., in which either the heavy chains, light chains, or both, are fusion proteins), and univalent antibodies (i.e., comprised of a heavy chain/light chain complex bound to the constant region of a second heavy chain). Also included are Fab fragments, including Fab′ and F(ab)2 fragments of antibodies. Methods for the production of all of the above types of antibodies and derivatives are well-known in the art and are discussed in more detail below. For example, techniques for producing and processing polyclonal antisera are disclosed in Mayer and Walker, 1987, Immunochemical Methods in Cell and Molecular Biology, (Academic Press, London). The general methodology for making monoclonal antibodies by hybridomas is well known. Immortal antibody-producing cell lines can be created by cell fusion, and also by other techniques such as direct transformation of B lymphocytes with oncogenic DNA, or transfection with Epstein-Barr virus. See, e.g., Schreier et al., 1980, Hybridoma Techniques; U.S. Pat. Nos. 4,341,761; 4,399,121; 4,427,783; 4,444,887; 4,466,917; 4,472,500; 4,491,632; and 4,493,890. Panels of monoclonal antibodies produced against peptides encoded by genes disclosed herein can be screened for various properties; i.e. for isotype, epitope affinity, etc.

The antibodies of this invention can be purified by standard methods, including but not limited to preparative disc-gel electrophoresis, isoelectric focusing, HPLC, reversed-phase HPLC, gel filtration, ion exchange and partition chromatography, and countercurrent distribution. Purification methods for antibodies are disclosed, e.g., in The Art of Antibody Purification, 1989, Amicon Division, W. R. Grace & Co. General protein purification methods are described in Protein Purification: Principles and Practice, R. K. Scopes, Ed., 1987, Springer-Verlag, New York, N.Y.

Methods for determining the immunogenic capability of the disclosed sequences and the characteristics of the resulting sequence-specific antibodies and immune cells are well-known in the art. For example, antibodies elicited in response to a peptide comprising a particular polymorphic sequence can be tested for their ability to specifically recognize that polymorphic sequence, i.e., to bind differentially to a peptide or polypeptide comprising the polymorphic sequence and thus distinguish it from a similar peptide or polypeptide containing a different sequence at the same position.

Kits

As set forth herein, the invention provides diagnostic methods, e.g., for determining the identity of the allelic variants of polymorphic regions present in the gene loci of genes disclosed herein, wherein specific allelic variants of the polymorphic region are associated with cardiovascular diseases. In a preferred embodiment, the diagnostic kit can be used to determine whether a subject is at risk of developing a cardiovascular disease. This information could then be used, e.g., to optimize treatment of such individuals.

In preferred embodiments, the kit comprises a probe or primer which is capable of hybridizing to a gene and thereby identifying whether the gene contains an allelic variant of a polymorphic region which is associated with a risk for cardiovascular disease. The kit preferably further comprises instructions for use in diagnosing a subject as having, or having a predisposition, towards developing a cardiovascular disease. The probe or primers of the kit can be any of the probes or primers described in this file.

Preferred kits for amplifying a region of a gene comprising a polymorphic region of interest comprise one, two or more primers.

Antibody-Based Diagnostic Methods and Kits:

The invention also provides antibody-based methods for detecting polymorphic patterns in a biological sample. The methods comprise the steps of: (i) contacting a sample with one or more antibody preparations, wherein each of the antibody preparations is specific for a particular polymorphic form of the proteins encoded by genes disclosed herein, under conditions in which a stable antigen-antibody complex can form between the antibody and antigenic components in the sample; and (ii) detecting any antigen-antibody complex formed in step (i) using any suitable means known in the art, wherein the detection of a complex indicates the presence of the particular polymorphic form in the sample.

Typically, immunoassays use either a labelled antibody or a labelled antigenic component (e.g., that competes with the antigen in the sample for binding to the antibody). Suitable labels include without limitation enzyme-based, fluorescent, chemiluminescent, radioactive, or dye molecules. Assays that amplify the signals from the probe are also known, such as, for example, those that utilize biotin and avidin, and enzyme-labelled immunoassays, such as ELISA assays.

The present invention also provides kits suitable for antibody-based diagnostic applications. Diagnostic kits typically include one or more of the following components:

(i) Polymorphism-specific antibodies. The antibodies may be pre-labelled; alternatively, the antibody may be unlabelled and the ingredients for labelling may be included in the kit in separate containers, or a secondary, labelled antibody is provided; and

(ii) Reaction components: The kit may also contain other suitably packaged reagents and materials needed for the particular immunoassay protocol, including solid-phase matrices, if applicable, and standards.

The kits referred to above may include instructions for conducting the test. Furthermore, in preferred embodiments, the diagnostic kits are adaptable to high-throughput and/or automated operation.

Drug Targets and Screening Methods

According to the present invention, nucleotide sequences derived from genes disclosed herein and peptide sequences encoded by genes disclosed herein, particularly those that contain one or more polymorphic sequences, comprise useful targets to identify cardiovascular drugs, i.e., compounds that are effective in treating one or more clinical symptoms of cardiovascular disease. Furthermore, especially when a protein is a multimeric protein that are build of two or more subunits, is a combination of different polymorphic subunits very useful.

Drug targets include without limitation (i) isolated nucleic acids derived from the genes disclosed herein, and (ii) isolated peptides and polypeptides encoded by genes disclosed herein, each of which comprises one or more polymorphic positions.

In Vitro Screening Methods:

In one series of embodiments, an isolated nucleic acid comprising one or more polymorphic positions is tested in vitro for its ability to bind test compounds in a sequence-specific manner. The methods comprise:

(i) providing a first nucleic acid containing a particular sequence at a polymorphic position and a second nucleic acid whose sequence is identical to that of the first nucleic acid except for a different sequence at the same polymorphic position;

(ii) contacting the nucleic acids with a multiplicity of test compounds under conditions appropriate for binding; and

(iii) identifying those compounds that bind selectively to either the first or second nucleic acid sequence.

Selective binding as used herein refers to any measurable difference in any parameter of binding, such as, e.g., binding affinity, binding capacity, etc.

In another series of embodiments, an isolated peptide or polypeptide comprising one or more polymorphic positions is tested in vitro for its ability to bind test compounds in a sequence-specific manner. The screening methods involve:

(i) providing a first peptide or polypeptide containing a particular sequence at a polymorphic position and a second peptide or polypeptide whose sequence is identical to the first peptide or polypeptide except for a different sequence at the same polymorphic position;

(ii) contacting the polypeptides with a multiplicity of test compounds under conditions appropriate for binding; and

(iii) identifying those compounds that bind selectively to one of the nucleic acid sequences.

In preferred embodiments, high-throughput screening protocols are used to survey a large number of test compounds for their ability to bind the genes or peptides disclosed above in a sequence-specific manner.

Test compounds are screened from large libraries of synthetic or natural compounds. Numerous means are currently used for random and directed synthesis of saccharide, peptide, and nucleic acid based compounds. Synthetic compound libraries are commercially available from Maybridge Chemical Co. (Trevillet, Cornwall, UK), Comgenex (Princeton, N.J.), Brandon Associates (Merrimack, N.H.), and Microsource (New Milford, Conn.). A rare chemical library is available from Aldrich (Milwaukee, Wis.). Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available from e.g. Pan Laboratories (Bothell, Wash.) or MycoSearch (N.C.), or are readily producible. Additionally, natural and synthetically produced libraries and compounds are readily modified through conventional chemical, physical, and biochemical means.

In Vivo Screening Methods:

Intact cells or whole animals expressing polymorphic variants of genes disclosed herein can be used in screening methods to identify candidate cardiovascular drugs.

In one series of embodiments, a permanent cell line is established from an individual exhibiting a particular polymorphic pattern. Alternatively, cells (including without limitation mammalian, insect, yeast, or bacterial cells) are programmed to express a gene comprising one or more polymorphic sequences by introduction of appropriate DNA. Identification of candidate compounds can be achieved using any suitable assay, including without limitation (i) assays that measure selective binding of test compounds to particular polymorphic variants of proteins encoded by genes disclosed herein; (ii) assays that measure the ability of a test compound to modify (i.e., inhibit or enhance) a measurable activity or function of proteins encoded by genes disclosed herein; and (iii) assays that measure the ability of a compound to modify (i.e., inhibit or enhance) the transcriptional activity of sequences derived from the promoter (i.e., regulatory) regions of genes disclosed herein.

In another series of embodiments, transgenic animals are created in which (i) one or more human genes disclosed herein, having different sequences at particular polymorphic positions are stably inserted into the genome of the transgenic animal; and/or (ii) the endogenous genes disclosed herein are inactivated and replaced with human genes disclosed herein, having different sequences at particular polymorphic positions. See, e.g., Coffman, Semin. Nephrol. 17:404, 1997; Esther et al., Lab. Invest. 74:953, 1996; Murakami et al., Blood Press. Suppl. 2:36, 1996. Such animals can be treated with candidate compounds and monitored for one or more clinical markers of cardiovascular status.

The following are intended as non-limiting examples of the invention.

Material and Methods

Genotyping of patient DNA with the Pyrosequencing™ Method as described in the patent application WO 9813523:

First a PCR is set up to amplify the flanking regions around a SNP. Therefor 2 ng of genomic DNA (patient sample) are mixed with a primerset (20-40 pmol) producing a 75 to 320 bp PCR fragment with 0, 3 to 1 U Qiagens Hot Star Taq Polymerase™ in a total volume of 20 μL. One primer is biotinylated depending on the direction of the sequencing primer. To force the biotinylated primer to be incorporated it is used 0, 8 fold.

For primer design, programms like Oligo 6™ (Molecular Biology Insights) or Primer Select™ (DNAStar) are used. PCR setup is performed by a BioRobot 3000™ from Qiagen. PCR takes place in T1 or Tgradient Thermocyclers™ from Biometra.

The whole PCR reaction is transferred into a PSQ plate™ (Pyrosequencing) and prepared using the Sample Prep Tool™ and SNP Reagent Kit™ from Pyrosequencing according to their instructions.

Preparation of Template for Pyrosequencing™:

Sample Preparation Using PSQ 96 Sample Prep Tool:

1. Mount the PSQ 96 Sample Prep Tool Cover onto the PSQ 96 Sample Prep Tool as follows: Place the cover on the desk, retract the 4 attachment rods by separating the handle from the magnetic rod holder, fit the magnetic rods into the holes of the cover plate, push the handle downward until a click is heard. The PSQ 96 Sample Prep Tool is now ready for use.

2. To transfer beads from one plate to another, place the covered tool into the PSQ 96 Plate containing the samples and lower the magnetic rods by separating the handle from the magnetic rod holder. Move the tool up and down a few times then wait for 30-60 seconds. Transfer the beads into a new PSQ 96 plate containing the solution of choice.

3. Release the beads by lifting the magnetic rod holder, bringing it together with the handle. Move the tool up and down a few times to make sure that the beads are released.

All steps are performed at room temperature unless otherwise stated.

Immobilization of PCR Product:

Biotinylated PCR products are immobilized on streptavidin-coated Dynabeads™ M-280 Streptavidin. Parallel immobilization of several samples are performed in the PSQ 96 Plate.

Mix PCR product, 20 μl of a well optimized PCR, with 25 μL 2× BW-buffer II. Add 60-150 μg Dynabeads. It is also possible to add a mix of Dynabeads and 2× BW-buffer II to the PCR product yielding a final BW-buffer II concentration of approximately 1×.

1. Incubate at 65° C. for 15 min agitation constantly to keep the beads dispersed. For optimal immobilization of fragments longer than 300 bp use 30 min incubation time.

Strand Separation:

4. For strand separation, use the PSQ 96 Sample Prep Tool to transfer the beads with the immobilized sample to a PSQ 96 Plate containing 50 μl 0.50 M NaOH per well. Release the beads.

5. After approximately 1 min, transfer the beads with the immobilized strand to a PSQ 96 Plate containing 99 μl 1× Annealing buffer per well and mix thoroughly.

6. Transfer the beads to a PSQ 96 Plate containing 45 μl of a mix of 1× Annealing buffer and 3-15 pmoles sequencing primer per well.

7. Heat at 80° C. for 2 minutes in the PSQ 96 Sample Prep Thermoplate and move to room temperature.

8. After reaching room temperature, continue with the sequencing reaction.

Sequencing Reaction:

1. Choose the method to be used (“SNP Method”) and enter relevant information in the PSQ 96 Instrument Control software.

2. Place the cartridge and PSQ 96 Plate in the PSQ 96 Instrument.

3. Start the run.

Genotyping Using the ABI 7700/7900 Instrument (TaqMan)

SNP genotypisation using the TaqMan (Applied Biosystems/Perkin Elmer) was performed according to the manufacturer's instructions. The TaqMan assay is discussed by Lee et al., Nucleic Acids Research 1993, 21: 3761-3766.

Genotyping with a Service Contractor:

Qiagen Genomics, formerly Rapigene, is a service contractor for genotyping SNPs in patient samples. Their method is based on a primer extension method where two complementary primers are designed for each genotype that are labeled with different tags. Depending on the genotype only one primer will be elongated together with a certain tag. This tag can be detected with mass spectrometry and is a measure for the respective genotype. The method is described in the following patent: “Detection and identification of nucleic acid molecules—using tags which may be detected by non-fluorescent spectrometry or potentiometry” (WO 9727325).

EXAMPLES

To exemplify the present invention and it's utility (the imaginary) baySNP 28 will be used in the following:

The nucleotide polymorphism found for baySNP 28 (e.g. C to T exchange) and the gene in which it presumably resides can be read from table 3. baySNP 28 was genotyped in various patient cohorts using primers as described in table 2. As a result the following number of patients carrying different genotypes were found (information combined from tables 3 and 5a):

Geno-Geno-Genotype
type 11type 1222
baySNPCohortTotal“CC”“CT”“TT”
28HELD_FEM_HIRESP12129
28HELD_FEM_LORESP223127

When comparing the number of female patients exhibiting a high response to statin therapy (HELD_FEM_HIRESP) with the control cohort (HELD_FEM_LORESP) it appears that the number of low responders carrying the CT genotype is increased. This points to a lower statin response among female individuals with the CT genotype. Applying statistical tests on those findings the following p-values were obtained (data taken from table 5b):

GTYPEGTYPEGTYPE
BAYSNPCOMPARISONCPVALXPVALLRPVAL
28HELD_FEM_EFF0.05060.05080.0442

As at least one of the GTYPE p values is below 0, 05 the association of genotype and statin response phenotype is regarded as statistically significant. I.e. the analysis of a patient's genotype can predict the response to statin therapy. In more detail one can calculate the relative risk to exhibit a certain statin response phenotype when carrying a certain genotype (data taken from table 6a):

BAYSNPCOMPARISONGTYPE1GTYPE2GTYPE3RR1RR2RR3
28HELD_FEM_EFFCCCTTT0.680.293.38

In case of baySNP 28 the risk to exhibit a high responder phenotype is 3, 38 times higher when carrying the TT genotype. This indicates that a TT polymorphism in baySNP 28 is an independent risk factor for high statin response in females. On the other hand carriers of a CT or CC genotype have a reduced risk of being a high responder.

In addition statistical associations can be calculated on the basis on alleles. This calculation would identify risk alleles instead of risk genotypes.

In case of baySNP 28 the following allele counts were obtained (data combined from tables 3 and 5a):

Allele 1Allele 2
baySNPCohortTotal“C”“T”
28HELD_FEM_HIRESP12420
28HELD_FEM_LORESP221826

When comparing the number of female patients with high statin response (HELD_FEM_HIRESP) with the control cohort (HELD_FEM_LORESP) it appears that the number of high responders carrying the T allele is increased, whereas the number of high responders carrying the C allele is diminished. This points to a higher statin response among female individuals with the T allele. Applying statistical tests on those findings the following p-values were obtained (data taken from table 5b):

ALLELEALLELEALLELE
BAYSNPCOMPARISONCPVALXPVALLRPVAL
28HELD_FEM_EFF0.04110.05790.0349

As at least one of the ALLELE p values is below 0, 05 the association of allele and statin response phenotype is regarded as statistically significant (in this example significant p values were obtained from two statistical tests). I.e. also the analysis of a patient's alleles from baySNP 28 can predict the extend of statin response. In more detail one can calculate the relative risk to exhibit a certain statin response phenotype when carrying a certain allele (data taken from table 6b):

baySNPAllele 1Allele 2COMPARISONRR1RR2
28CTHELD_FEM_EFF0.422.39

In case of baySNP 28 the risk to exhibit a high responder phenotype is 2, 39 times higher when carrying the T allele. This indicates that the T allele of baySNP28 is an independent risk factor for a high statin response in females. In other words those patients should receive lower doses of statins in order to avoid ADR. However due to their ‘high responder’ phenotype they will still benefit from the drug. In turn carriers of the C allele should receive higher drug doses in order to experience a beneficial therapeutic effect.

Another example is (the imaginary) baySNP 29, which is taken to exemplify polymorphisms relevant for adverse drug reactions. baySNP 29 was found significant when comparing male patients with severe ADR to the respective controls (as defined in table 1b).

The relative risk ratios for the genotypes AA, AG and GG were as follows (data taken from table 6a):

BAYSNPCOMPARISONGTYPE1GTYPE2GTYPE3RR1RR2RR3
29HELD_MAL_ADR5ULNAAAGGG3.150.660.32

In this case male patients carrying the AA genotype have a 3, 15 times higher risk to suffer from ADR. In other words those patients should either receive lower doses of statins or switch to an alternative therapy in order to avoid ADR. On the other hand male patients with AG or GG genotypes appear to be more resistant to ADR and hence better tolerate statin therapy.

As can be seen from the following tables some of the associations that are disclosed in the present invention are indicative for more than one phenotype. Some baySNPs can for example be linked to ADR, but also to the risk to suffer from CVD (table 6).

TABLE 1a
Definition of “good” and “bad” serum lipid levels
“Good”“Bad”
LDL-Cholesterol [mg/dL]125-150170-200
Cholesterol [mg/dL]190-240265-315
HDL-Cholesterol [mg/dL] 60-10530-55
Triglycerides [mg/dL] 45-115170-450

TABLE 1b
Definition of drug response phenotypes
Low responderDecrease of serum LDL of at least 10% and at most
50% upon administration of 0.8 mg Cerivastatin
(female patients)
High responderDecrease of serum LDL of at least 50% upon
administration of 0.4 mg Cerivastatin (female
patients)
Very low responderDecrease of serum LDL of at least 10% and at most
35% upon administration of 0.8 mg Cerivastatin
(female patients)
Very high responderDecrease of serum LDL of at least 55% upon
administration of 0.4 mg Cerivastatin (female
patients)
Ultra low responderDecrease of serum LDL of at least 10% and at most
25% upon administration of 0.8 mg Cerivastatin
(female patients)
Ultra high responderDecrease of serum LDL of at least 60% upon
administration of 0.4 mg Cerivastatin (female
patients)
Tolerant patientNo diagnosis of muscle cramps, muscle pain,
muscle weakness, myalgia or myopathy
AND
serum CK levels below 70 U/l in women and below
80 U/l in men.
ADR patientDiagnosis of muscle cramps, muscle pain, muscle
(CK increase at least 2 × ULN)weakness, myalgia or myopathy
OR
serum CK levels higher than 140 U/l in women and
160 U/l in men.
Advanced ADR patient [ADR3]Serum CK levels higher than 210 U/l in women and
(advanced CK increase, at least 3 × ULN)*240 U/l in men
Severe ADR patient [ADR5]Serum CK levels higher than 350 U/l in women and
(severe CK increase, at least 5 × ULN)*400 U/l in men

*When assembling the cohorts for advanced and severe ADR we focused on the CK serum levels as those provide a more independent measure of statin related ADR.

TABLE 1c
Definition of “high” and “low” serum HDL cholesterol levels
MaleFemale
individualsindividuals
‘High’ HDL-Cholesterol [mg/dL]>=80>=104
‘Low’ HDL-Cholesterol [mg/dL]<=35<=37

An informed consent was signed by the patients and control people. Blood was taken by a physician according to medical standard procedures.

Samples were collected anonymous and labeled with a patient number.

DNA was extracted using kits from Qiagen.

TABLE 2
Oligonucleotide primers used for genotyping
Depending on the method used for genotyping different oligonucleotides were utilized.
The table lists the various methods and primer sets that were used for this invention.
Primers were designed using suitable programs like Primer Express ™ (Applied
Biosystems, Darmstadt, Germany) or Oligo ™ (Molecular Biology Insights, Inc.,
Cascade, CO, USA).
No. of
MethodoligonucleotidesType of oligonucletides
Mass Spectrometry42 Primers for preamplification of the genomic
fragment,
2 allele specific primers with additional tag
sequences for subsequent allele spec. PCR
Pyrosequencing ™32 Primers for preamplification of the genomic
fragment (one biotinylated), 1 sequencing primer
TaqMan42 Primers for amplification of the genomic
fragment, 2 allele specific probes carrying
different fluorochromes (VIC, FAM) and a
quencher. Preferably the allele specific probes
have a minor groove binder (MGB) attached
(Kutyavin et al., Nucleic Acids Research 2000,
28: 655-661).

TABLE 3
PA SNPs, SNP classes and putative PA genes
The baySNP number refers to an internal numbering of the PA SNPs. Listed are the different polymorphisms found in our association
study. Also from the association study we defined SNP classes; with ADR being adverse drug reaction related, with EFF being drug
efficacy related and CVD being cardiovascular disease related. ADR3 and ADR5 relate to advanced and severe ADR, whereas VEFF
and UEFF relate to very high/low and ultra high/low drug efficacy (see table 1b). Also accession numbers and descriptions of those
gene loci are given that are most homologous to the PA genes as listed in the sequences section (see below). Homologous genes
and their accession numbers could be found by those skilled in the art in the Genbank database. The term ‘SECONDARY’
marks SNPs that do not reside inside the respective gene, but in it's proximity. Null: not defined.
SNP
BAYSNPclassGTYPE11GTYPE12GTYPE22NCBIDESCRIPTION
160ADR3TTCTCCHS34804Human thermostable phenol sulfotransferase (STP2) gene, partial cds.
194ADR5GGCGCCL33075Homo sapiens ras GTPase-activating-like
protein (IQGAP1) mRNA, complete cds.
194EFFGGCGCCL33075Homo sapiens ras GTPase-activating-like
protein (IQGAP1) mRNA, complete cds.
411ADR5AAATTTHS34804Human thermostable phenol sulfotransferase (STP2) gene, partial cds.
466ADRCCCTTTM33519Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
466ADR5CCCTTTM33519Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
555CVDAAAGGGHS34804Human thermostable phenol sulfotransferase (STP2) gene, partial cds.
623ADR3CCCTTTABCB3TAP2: transporter 2, ATP-binding cassette, sub-family B (MDR/TAP)
625ADR3CCCTTTU63721transporter 1, ATP-binding cassette, sub-family B (MDR/TAP)
777CVDCCCTTTU63721LIMK1: LIM domain kinase 1
1005CVDAAAGGGO60443CACNA2D2: calcium channel, voltage-dependent, alpha 2/delta subunit 2
1062CVDGGAGAAM17262DFNA5: deafness, autosomal dominant 5
1275CVDCCCGGGM17262Homo sapiens TNFa and gene for tumor
necrosis factor and TNFb gene for lymphotoxin
1669CVDTTCTCCAC004511F2: coagulation factor II (thrombin)
1755CVDAAAGGGAC004511Human protein C inhibitor gene, complete cds.
1765CVDAAAGGGM29932Human Na,K-ATPase subunit alpha 2 (ATP1A2) gene, complete cds.
2109CVDAAAGGGM29932TFAP2B: transcription factor AP-2 beta
(activating enhancer binding protein 2 beta)
2150CVDTTCTCCM29932CSF2: colony stimulating factor 2 (granulocyte-macrophage)
IL3: interleukin 3 (colony-stimulating
factor, multiple)
2234CVDTTGTGGX06562Homo sapiens PAC clone RP1-102K2
from 22q12.1-qter, complete sequence.
2321CVDGGGTTTX06562ADRB3: adrenergic, beta-3-, receptor
2354CVDCCCTTTX06562Human endothelial leukocyte adhesion
molecule 1 (ELAM-1) mRNA, complete cds.
3451ADRCCCTTTX62996Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
3451ADR5CCCTTTX62996Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
3452ADR5AAAGGGBC014081Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
3453ADRCCCTTTNM_000927Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
4912CVDGGAGAANM_000927Human vascular endothelial growth factor gene, exon 1.
5093CVDGGAGAASECONDARY:BRD3: bromodomain containing 3
M34551
6333ADR5AAACCCSECONDARY:GHR: growth hormone receptor
M95724
6333ADRAAACCCSECONDARY:GHR: growth hormone receptor
AB043943
6333ADR3AAACCCSECONDARY:GHR: growth hormone receptor
AB043943
6333CVDAAACCCSECONDARY:GHR: growth hormone receptor
AB043943
7407ADR5GGAGAASECONDARY:Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
AB043943
7407ADRGGAGAASECONDARY:Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
AB043943
7407ADR3GGAGAASECONDARY:Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
AF065214
10584ADRGGGTTTAF129756Apolipoprotein M
10584ADR3GGGTTTAF129756Apolipoprotein M
11021CVDTTCTCCM60092Human myoadenylate deaminase (AMPD1) mRNA, complete cds.
11062ADR5TTCTCCAB055890Homo sapiens c-lbc mRNA for guanine
nucleotide exchange factor Lbc, complete cds.
11147ADRCCCTTTU51903Human RasGAP-related protein (IQGAP2) mRNA, complete cds.
11212CVDGGCGCCX06290Human mRNA for apolipoprotein(a)
11371ADR3AAAGZ82215Human DNA sequence from clone RP1-68O2 on chromosome
22 Contains the 5′ end of the APOL2 gene for apolipoprotein L 2,
the APOL gene for apolipoprotein L, the MYH9 gene for nonmuscle
type myosin heavy chain 9. ESTs, STSs and GSSs.
11371ADRAAAGZ82215Human DNA sequence from clone RP1-68O2 on chromosome
22 Contains the 5′ end of the APOL2 gene for apolipoprotein L 2,
the APOL gene for apolipoprotein L, the MYH9 gene for nonmuscle
type myosin heavy chain 9. ESTs, STSs and GSSs.
11487UEFFTTATAAM75106Human prepro-plasma carboxypeptidase B mRNA, complete cds.
11585CVDGGGTTTAC073593Homo sapiens 12 BAC RP11-13J12 (Roswell Park Cancer
Institute Human BAC Library) complete sequence.
11683UEFFCCCGGGNM_002575serine (or cysteine) proteinase inhibitor, clade B (ovalbumin), member 2
11863VEFFGGAGAANM_000927ATP-binding cassette, sub-family B (MDR/TAP), member 1
12024ADRCCCTTTAF129756BAT5
12024ADR3CCCTTTAF129756BAT5
12632ADR5CCCTTTNM_000593transporter 1, ATP-binding cassette, sub-family B (MDR/TAP)
13994CVDGGAGAAX62996MTND4L: NADH dehydrogenase 4L
13994ADRGGAGAAX62996MTND4L: NADH dehydrogenase 4L
14090EFFCCACAAAF044954Homo sapiens NADH:ubiquinone oxidoreductase PDSW
subunit mRNA, nuclear gene encoding mitochondrial
protein, complete cds.
14159EFFTTCTCCAB014521Homo sapiens mRNA for KIAA0621 protein, partial cds.
14362UEFFTTGTGGX66401TAP1: transporter 1, ATP-binding cassette, sub-family B (MDR/TAP)
14410ADRGGAGAF057557Homo sapiens P-glycoprotein (MDR1) gene, exon 10 and partial cds.
14488ADRAAAGAF057557BAT3
14488ADR3AAAGAF057557BAT3
14490ADR5CCCTTTNM_013374Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
14490ADR3CCCTTTM33519Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
14493ADRAAAGAF129756BAT4
14493ADR3AAAGAF129756BAT4
14554ADR3CCACAAU52111H. sapiens creatine transporter gene
14554ADR5CCACAAU52111H. sapiens creatine transporter gene
14554ADRCCACAAU52111H. sapiens creatine transporter gene
14603CVDAAAGX04981H. sapiens gene for lecithin-cholesterol acyltransferase (LCAT)
14820VEFFAAAGGGBC008915SERPINA5
14820UEFFAAAGGGBC008915SERPINA5
14876EFFCCCTTTNM_005138Homo sapiens SCO cytochrome oxidase deficient
homolog 2 (yeast) (SCO2), nuclear gene encoding
mitochondrial protein, mRNA.
14876VEFFCCCTTTNM_005138Homo sapiens SCO cytochrome oxidase deficient
homolog 2 (yeast) (SCO2), nuclear gene encoding
mitochondrial protein, mRNA.
14954ADRGGCGCCAF044954Homo sapiens NADH:ubiquinone oxidoreductase PDSW
subunit mRNA, nuclear gene encoding mitochondrial
protein, complete cds.
14957ADR5AAACCCAF047181Homo sapiens NADH-ubiquinone oxidoreductase
subunit CI-SGDH mRNA, complete cds.
14957VEFFAAACCCAF047181Homo sapiens NADH-ubiquinone oxidoreductase
subunit CI-SGDH mRNA, complete cds.
14977UEFFAAAGGGBC003093Homo sapiens, Rab geranylgeranyltransferase, alpha
subunit, clone MGC: 1485 IMAGE: 3537388, mRNA, complete cds.
15349ADRCCCTTTU51903Human RasGAP-related protein (IQGAP2) mRNA, complete cds.
15590ADR5GGAGAAHSKINAANPH. sapiens mRNA for kinase A anchor protein
15590ADRGGAGAAHSKINAANPH. sapiens mRNA for kinase A anchor protein
16268ADR5CCCGGGU20158Human 76 kDa tyrosine phosphoprotein SLP-76 mRNA, complete cds.
36078VEFFAAAGNM_000927ABCB1: ATP-binding cassette, sub-family B (MDR/TAP), member 1
36078EFFAAAGNM_000927ABCB1: ATP-binding cassette, sub-family B (MDR/TAP), member 1
36406ADR5TTCTCCJ02973Human thrombomodulin gene, complete cds.
37135ADR3CCCTTTAJ276180Homo sapiens partial ZNF202 gene for zinc finger protein homolog, exon 4
37135ADR5CCCTTTAJ276180Homo sapiens partial ZNF202 gene for zinc finger protein homolog, exon 4
37327CVDTTCTCCM27111Human PLP gene encoding proteolipid protein, upstream region.
37327VEFFTTCTCCM27111Human PLP gene encoding proteolipid protein, upstream region.
37327UEFFTTCTCCM27111Human PLP gene encoding proteolipid protein, upstream region.
37327ADRTTCTCCM27111Human PLP gene encoding proteolipid protein, upstream region.
37404ADRTTCTCCM63971Human vascular endothelial growth factor gene, exon 1.
37413ADR5AAATTTM74775Human lysosomal acid lipase/cholesteryl esterase mRNA, complete cds.
37413ADR3AAATTTM74775Human lysosomal acid lipase/cholesteryl esterase mRNA, complete cds.
37939EFFCCCTTTV00595Human mRNA encoding prothrombin.
37939CVDCCCTTTV00595Human mRNA encoding prothrombin.
38009ADRTTGTGGAJ000414Homo sapiens mRNA for Cdc42-interacting protein 4 (CIP4)
40004CVDGGCGCCAF070652Homo sapiens NADH-ubiquinone oxidoreductase
subunit B14.5B homolog mRNA, complete cds.
40522ADRTTATAAAF058921Homo sapiens cytosolic phospholipase A2-gamma mRNA, complete cds.
40522ADR3TTATAAAF058921Homo sapiens cytosolic phospholipase A2-gamma mRNA, complete cds.
40522ADR5TTATAAAF058921Homo sapiens cytosolic phospholipase A2-gamma mRNA, complete cds.
41847EFFTTGTGGL33075Homo sapiens ras
GTPase-activating-like protein (IQGAP1) mRNA, complete cds.
42084ADR5AAACCCM21574Human platelet-derived growth factor
receptor alpha (PDGFRA) mRNA, complete cds.
42084ADR3AAACCCM21574Human platelet-derived growth factor
receptor alpha (PDGFRA) mRNA, complete cds.
42084ADRAAACCCM21574Human platelet-derived growth factor
receptor alpha (PDGFRA) mRNA, complete cds.
42677ADR3CCCGGGU51903Human RasGAP-related protein (IQGAP2) mRNA, complete cds.
42677ADR5CCCGGGU51903Human RasGAP-related protein (IQGAP2) mRNA, complete cds.
42677ADRCCCGGGU51903Human RasGAP-related protein (IQGAP2) mRNA, complete cds.
46865VEFFTTCTCCL15189heat shock 70 kDa protein 9B (mortalin-2)
46865EFFTTCTCCL15189heat shock 70 kDa protein 9B (mortalin-2)
46865ADR5TTCTCCL15189heat shock 70 kDa protein 9B (mortalin-2)
47856ADR5TTCTCCM14333Homo sapiens c-syn protooncogene mRNA, complete cds.
47856VEFFTTCTCCM14333Homo sapiens c-syn protooncogene mRNA, complete cds.
48490CVDAAAGGGM31158Human cAMP-dependent protein
kinase subunit RII-beta mRNA, complete cds.
48490ADR3AAAGGGM31158Human cAMP-dependent protein
kinase subunit RII-beta mRNA, complete cds.
48490ADRAAAGGGM31158Human cAMP-dependent protein
kinase subunit RII-beta mRNA, complete cds.
50164ADR3GGAGAAU02570Human CDC42 GTPase-activating protein mRNA, partial cds.
50164ADRGGAGAAU02570Human CDC42 GTPase-activating protein mRNA, partial cds.
50164ADR5GGAGAAU02570Human CDC42 GTPase-activating protein mRNA, partial cds.
54704ADRGGAGAAX97548H. sapiens mRNA for TIF1beta zinc finger protein
54806CVDGGAGAAY00698Human mRNA for muscle phosphofructokinase (E.C. 2.7.1.11)
54806UEFFGGAGAAY00698Human mRNA for muscle phosphofructokinase (E.C. 2.7.1.11)
54807ADR5GGAGAAY00698Human mRNA for muscle phosphofructokinase (E.C. 2.7.1.11)
54807ADRGGAGAAY00698Human mRNA for muscle phosphofructokinase (E.C. 2.7.1.11)
54807ADR3GGAGAAY00698Human mRNA for muscle phosphofructokinase (E.C. 2.7.1.11)
54807EFFGGAGAAY00698Human mRNA for muscle phosphofructokinase (E.C. 2.7.1.11)
54807UEFFGGAGAAY00698Human mRNA for muscle phosphofructokinase (E.C. 2.7.1.11)
55733CVDGGAGAANM_021151Homo sapiens carnitine O-octanoyltransferase (CROT), mRNA.
55733VEFFGGAGAANM_021151Homo sapiens carnitine O-octanoyltransferase (CROT), mRNA.
55733ADRGGAGAANM_021151Homo sapiens carnitine O-octanoyltransferase (CROT), mRNA.
55846VEFFAAAGGGSECONDARY:SSA1: Sjogren syndrome antigen A1 (52 kDa,
ribonucleoprotein autoantigen SS-A/Ro) M34551
55846UEFFAAAGGGSECONDARY:SSA1: Sjogren syndrome antigen A1 (52 kDa,
ribonucleoprotein autoantigen SS-A/Ro) M34551
55906EFFGGGTTTSECONDARY:CENPC1: centromere protein C 1
M95724
56084UEFFCCCTTTSECONDARY:AD024 protein
ABCB11
57818ADRGGAGAASECONDARY:PPP1R12C: protein phosphatase 1, regulatory (inhibitor) subunit 12C
AB043943
57818ADR3GGAGAASECONDARY:PPP1R12C: protein phosphatase 1, regulatory (inhibitor) subunit 12C
AB043943
57818EFFGGAGAASECONDARY:PPP1R12C: protein phosphatase 1, regulatory (inhibitor) subunit 12C
AB043943
57819ADRTTCTCCSECONDARY:PPP1R12C: protein phosphatase 1, regulatory
(inhibitor) subunit 12C Proteome Summary: AB043943
57819EFFTTCTCCSECONDARY:PPP1R12C: protein phosphatase 1, regulatory
(inhibitor) subunit 12C Proteome Summary: AB043943
57828VEFFAAAGGGSECONDARY:PPP1R12C: protein phosphatase 1, regulatory
(inhibitor) subunit 12C Proteome Summary: AB043943
57987ADR5TTCTCCSECONDARY:PLA2G4C: phospholipase A2, group IVC (cytosolic, calcium-independent)
AF065214
59456ADR3AAACCCHS.150207Homo sapiens UDP
glycosyltransferase 2 family, polypeptide B15 (UGT2B15), mRNA.
59460UEFFTTCTCCAB055890Homo sapiens c-lbc mRNA for guanine
nucleotide exchange factor Lbc, complete cds.
59461ADR5CCCTTTAB055890Homo sapiens c-lbc mRNA for guanine
nucleotide exchange factor Lbc, complete cds.
59461UEFFCCCTTTAB055890Homo sapiens c-lbc mRNA for guanine
nucleotide exchange factor Lbc, complete cds.
59461EFFCCCTTTAB055890Homo sapiens c-lbc mRNA for guanine
nucleotide exchange factor Lbc, complete cds.
60900ADR3AAAGGGAB042237Homo sapiens Borg4 mRNA, complete cds.
60900ADRAAAGGGAB042237Homo sapiens Borg4 mRNA, complete cds.
60902ADRAAATTTAB042237Homo sapiens Borg4 mRNA, complete cds.
60934CVDCCCTTTAF037439Homo sapiens protein kinase A anchoring protein mRNA, complete cds.
60934ADRCCCTTTAF037439Homo sapiens protein kinase A anchoring protein mRNA, complete cds.
60957ADR5GGAGAAAF128625Homo sapiens CDC42-binding
protein kinase beta (CDC42BPB) mRNA, complete cds.
60957ADR3GGAGAAAF128625Homo sapiens CDC42-binding protein
kinase beta (CDC42BPB) mRNA, complete cds.
60959ADR3TTCTCCAF128625Homo sapiens CDC42-binding protein
kinase beta (CDC42BPB) mRNA, complete cds.
60959ADR5TTCTCCAF128625Homo sapiens CDC42-binding protein
kinase beta (CDC42BPB) mRNA, complete cds.
60959ADRTTCTCCAF128625Homo sapiens CDC42-binding protein
kinase beta (CDC42BPB) mRNA, complete cds.
60962ADR5CCCTTTAF128625Homo sapiens CDC42-binding protein
kinase beta (CDC42BPB) mRNA, complete cds.
60962ADR3CCCTTTAF128625Homo sapiens CDC42-binding protein
kinase beta (CDC42BPB) mRNA, complete cds.
60962ADRCCCTTTAF128625Homo sapiens CDC42-binding protein
kinase beta (CDC42BPB) mRNA, complete cds.
60974ADR5GGAGAAAF130249Homo sapiens PAC 126N20 derived from
chromosome 21p11.2, complete sequence, containing
STCH and an unknown gene.
60978ADRGGCGCCAF163840Homo sapiens CRIB-containing
BORG1 protein (BORG1) mRNA, complete cds.
60978EFFGGCGCCAF163840Homo sapiens CRIB-containing BORG1
protein (BORG1) mRNA, complete cds.
60978VEFFGGCGCCAF163840Homo sapiens CRIB-containing BORG1
protein(BORG1) mRNA, complete cds.
60999ADR5GGGTTTAH006714Human muscle glycogen phosphorylase (PYGM) gene, 5′UTR and exon 1.
61011CVDTTCTCCAJ001515Homo sapiens mRNA for ryanodine receptor 3, complete CDS
61011EFFTTCTCCAJ001515Homo sapiens mRNA for ryanodine receptor 3, complete CDS
61086ADRGGAGAAAL136842Homo sapiens mRNA; cDNA DKFZp434A0530
(from clone DKFZp434A0530); complete cds
61126ADRCCCTTTD88460Homo sapiens mRNA for N-WASP, complete cds.
61126VEFFCCCTTTD88460Homo sapiens mRNA for N-WASP, complete cds.
61126UEFFCCCTTTD88460Homo sapiens mRNA for N-WASP, complete cds.
61126EFFCCCTTTD88460Homo sapiens mRNA for N-WASP, complete cds.
61137ADRTTCTCCL20969Homo sapiens cyclic AMP phosphodiesterase mRNA, complete cds.
61147EFFGGAGAAM13975Homo sapiens protein kinase C
beta-II type (PRKCB1) mRNA, complete cds.
61176ADR5AAAGGGM82814Homo sapiens GAP-related protein (NF1) mRNA, complete cds.
61176ADRAAAGGGM82814Homo sapiens GAP-related protein (NF1) mRNA, complete cds.
61176ADR3AAAGGGM82814Homo sapiens GAP-related protein (NF1) mRNA, complete cds.
61184ADR5CCCTTTNM_000295Homo sapiens serine (or cysteine) proteinase inhibitor, clade
A (alpha-1 antiproteinase, antitrypsin), member 1 (SERPINA1), mRNA.
61184ADRCCCTTTNM_000295Homo sapiens serine (or cysteine) proteinase inhibitor, clade A
(alpha-1 antiproteinase, antitrypsin), member 1 (SERPINA1), mRNA.
61197ADR3AAAGGGNM_001093Homo sapiens acetyl-Coenzyme A carboxylase beta (ACACB), mRNA.
61270ADR3AAAGGGU24153Homo sapiens p21-activated protein kinase (Pak2) mRNA, complete cds.
61270ADR5AAAGGGU24153Homo sapiens p21-activated protein kinase (Pak2) mRNA, complete cds.
61270CVDAAAGGGU24153Homo sapiens p21-activated protein kinase (Pak2) mRNA, complete cds.
61272ADR5AAAGGGU24153Homo sapiens p21-activated protein kinase (Pak2) mRNA, complete cds.
61272ADRAAAGGGU24153Homo sapiens p21-activated protein kinase (Pak2) mRNA, complete cds.
61284EFFGGAGAAU43522Human cell adhesion kinase beta (CAKbeta) mRNA, complete cds.
61292EFFGGAGAAU43522Human cell adhesion kinase beta (CAKbeta) mRNA, complete cds.
61292ADRGGAGAAU43522Human cell adhesion kinase beta (CAKbeta) mRNA, complete cds.
61297CVDTTCTCCU48449Human skeletal muscle ryanodine receptor
gene (RYR1), promoter region and exon 1.
61324VEFFGGAGAAX51985Human LAG-3 mRNA for CD4-related protein
involved in lymphocyte activation
61328EFFAAAGGGX52220Human FKBP mRNA for FK-506 binding protein
61373ADRGGCGCCZ29630H. sapiens syk mRNA for protein-tyrosine kinase
900066CVDCCCTTTAF275948ABCA1: ATP-binding cassette, sub-family
A (ABC1), member 1 - SNP HTM2
900071UEFFGGCGCCAF275948ABCA1: ATP-binding cassette, sub-family
A (ABC1), member 1 - SNP HTM3
900072UEFFGGCGCCAF275948ABCA1: ATP-binding cassette, sub-family
A (ABC1), member 1 - SNP HTM4
900072CVDGGCGCCAF275948ABCA1: ATP-binding cassette, sub-family
A (ABC1), member 1 - SNP HTM4
900072VEFFGGCGCCAF275948ABCA1: ATP-binding cassette, sub-family
A (ABC1), member 1 - SNP HTM4
900073ADRGGCGCCAF275948ABCA1: ATP-binding cassette, sub-family
A (ABC1), member 1 - SNP HTM15
900073CVDGGCGCCAF275948ABCA1: ATP-binding cassette, sub-family
A (ABC1), member 1 - SNP HTM15
900073ADR3GGCGCCAF275948ABCA1: ATP-binding cassette, sub-family
A (ABC1), member 1 - SNP HTM15
900073EFFGGCGCCAF275948ABCA1: ATP-binding cassette, sub-family
A (ABC1), member 1 - SNP HTM15
900074CVDCCCTTTAF275948ABCA1: ATP-binding cassette, sub-family
A (ABC1), member 1 - SNP HTM18
900074UEFFCCCTTTAF275948ABCA1: ATP-binding cassette, sub-family
A (ABC1), member 1 - SNP HTM18
900083EFFAAAGGGAF047182Homo sapiens NADH-ubiquinone oxidoreductase
subunit CI-B14 mRNA, complete cds.
900115ADR3AAAGGGU96781ATP2A1: ATPase, Ca++ transporting, cardiac muscle, fast twitch 1
900115CVDAAAGGGU96781ATP2A1: ATPase, Ca++ transporting, cardiac muscle, fast twitch 1
900115ADR5AAAGGGU96781ATP2A1: ATPase, Ca++ transporting, cardiac muscle, fast twitch 1
900143ADR5GGGTTTAC008945Selenoprotein P genomic region
900143ADRGGGTTTAC008945Selenoprotein P genomic region
900143ADR3GGGTTTAC008945Selenoprotein P genomic region
900173ADR3TTGTGGM76722H. sapiens lipoprotein lipase (LPL) gene, exons
7, 8, and 9, and an Alu repetative element.
900174ADR3AAAGGGU96781Human Ca2+ ATPase of fast-twitch skeletal muscle
sarcoplasmic reticulum adult and neonatal isoforms (ATP2A1) gene, exons
16 to 23 and complete cds.
900174ADR5AAAGGGU96781Human Ca2+ ATPase of fast-twitch skeletal muscle
sarcoplasmic reticulum adult and neonatal isoforms (ATP2A1) gene, exons
16 to 23 and complete cds.
900174CVDAAAGGGU96781Human Ca2+ ATPase of fast-twitch skeletal muscle
sarcoplasmic reticulum adult and neonatal isoforms (ATP2A1) gene, exons
16 to 23 and complete cds.
900175EFFGGAGAANM_003455Homo sapiens zinc finger protein 202 (ZNF202)
900180CVDGGAGAANM_005449TOSO: regulator of Fas-induced apoptosis
900221ADRGGCGCCNM_0013374PDCD6IP: programmed cell death 6 interacting protein
900250ADR5CCCTTTAC011254UGT2A1: UDP glycosyltransferase 2 family, polypeptide A1
900342ADRGGAGAANM_017646TRIT1: tRNA isopentenyltransferase 1
900344ADRAAACCCNM_017646TRIT1: tRNA isopentenyltransferase 1
900344ADR3AAACCCNM_017646TRIT1: tRNA isopentenyltransferase 1
900344ADR5AAACCCNM_017646TRIT1: tRNA isopentenyltransferase 1
10000001CVDGGAGAAM32992Cholesteryl ester transfer protein (CETP)
10000002CVDAAAGGGM32992Cholesteryl ester transfer protein (CETP)
10000017CVDTTCTCCM10065Human apolipoprotein E (epsilon-4 allele) gene, complete cds.

TABLE 4
Cohorts
Given are names (as used in table 5) and formations of the various cohorts that were used for
genotyping
COHORTDefinition
HELD_ALL_GOOD/BADHealthy elderly individuals of both genders with good or bad serum lipid
profiles (as defined in table 1a)
HELD_FEM_GOOD/BADHealthy elderly individuals (female) with good or bad serum lipid
profiles (as defined in table 1a)
HELD_MAL_GOOD/BADHealthy elderly individuals (male) with good or bad serum lipid profiles
(as defined in table 1a)
CVD_ALL_CASE/CTRLIndividuals with diagnosis of cardiovascular disease and healthy controls
(both genders)
CVD_FEM_CASE/CTRLIndividuals with diagnosis of cardiovascular disease and healthy controls
(female)
CVD_MAL_CASE/CTRLIndividuals with diagnosis of cardiovascular disease and healthy controls
(male)
HELD_FEM_ADRCTRLFemale individuals that tolerate adminstration of cerivastatin without
exhibiting signs of ADR (as defined in table 1b)
HELD_FEM_ADRCASEFemale individuals that exhibited ADR (as defined in table 1b) upon
administration of cerivastatin
HELD_MAL_ADRCTRLMale individuals that tolerate adminstration of cerivastatin without
exhibiting signs of ADR (as defined in table 1b)
HELD_MAL_ADRCASEMale individuals that exhibited ADR (as defined in table 1b) upon
administration of cerivastatin
HELD_ALL_ADRCTRLIndividuals of both genders that tolerate adminstration of cerivastatin
without exhibiting signs of ADR (as defined in table 1b)
HELD_ALL_ADRCASEIndividuals of both genders that exhibited ADR (as defined in table 1b)
upon administration of cerivastatin
HELD_FEM_LORESPFemale individuals with a minor response to cerivastatin administration
(as defined in table 1b)
HELD_FEM_HIRESPFemale individuals with a high response to to cerivastatin administration
(as defined in table 1b)
HELD_FEM_HIHDL/LOHDLHealthy elderly individuals (female) with high or low serum HDL
cholesterol levels (as defined in table 1c)
HELD_MAL_HIHDL/LOHDLHealthy elderly individuals (male) with high or low serum HDL
cholesterol levels (as defined in table 1c)
HELD_ALL_HIHDL/LOHDLHealthy elderly individuals of both genders with high or low serum HDL
cholesterol levels (as defined in table 1c)
HELD_FEM_ADR3CASEFemale individuals that exhibited advanced ADR (as defined in table
1b) upon administration of cerivastatin
HELD_MAL_ADR3CASEMale individuals that exhibited advanced ADR (as defined in table 1b)
upon administration of cerivastatin
HELD_ALL_ADR3CASEIndividuals of both genders that exhibited advanced ADR (as defined in
table 1b) upon administration of cerivastatin
HELD_FEM_VLORESPFemale individuals with a very low response to cerivastatin
administration (as defined in table 1b)
HELD_FEM_VHIRESPFemale individuals with a very high response to cerivastatin
administration (as defined in table 1b)
HELD_FEM_ADR5CASEFemale individuals that exhibited severe ADR (as defined in table 1b)
upon administration of cerivastatin
HELD_MAL_ADR5CASEMale individuals that exhibited severe ADR (as defined in table 1b)
upon administration of cerivastatin
HELD_ALL_ADR5CASEIndividuals of both genders that exhibited severe ADR (as defined in
table 1b) upon administration of cerivastatin
HELD_FEM_ULORESPFemale individuals with a ultra low response to cerivastatin
administration (as defined in table 1b)
HELD_FEM_UHIRESPFemale individuals with a ultra high response to to cerivastatin
administration (as defined in table 1b)

Table 5a and 5b Cohort Sizes and p-Values of PA SNPs

The baySNP number refers to an internal numbering of the PA SNPs. Cpval denotes the classical Pearson chi-squared test, Xpval denotes the exact version of Pearson's chi-squared test, LRpval denotes the likelihood-ratio chi-squared test. Cpvalue, Xpvalue, and LRpvalue are calculated as described in (SAS/STAT User's Guide of the SAS OnlineDoc, Version 8), (L. D. Fisher and G. van Belle, Biostatistics, Wiley Interscience 1993), and (A. Agresti, Statistical Science 7, 131 (92)). The GTYPE and Allele p values were obtained through the respective chi square tests when comparing COHORTs A and B. For GTYPE p value the number of patients in cohort A carrying genotypes 11, 12 or 22 (FQ11 A, FQ 12 A, FQ 22 A; genotypes as defined in table 3) were compared with the respective patients in cohort B (FQ11 B, FQ 12 B, FQ 22 B; genotypes as defined in table 3) resulting in the respective chi square test with a 3×2 matrix. For Allele p values we compared the allele count of alleles 1 and 2 (A1 and A2) in cohorts A and B, respectively (chi square test with a 2×2 matrix). SIZE A and B: Number of patients in cohorts A and B, respectively. See table 4 for definition of COHORTs A and B.

TABLE 5a
Cohort sizes and frequency of alleles and genotypes
baySNPA1A2COHORT_ASIZE_AFQ1 AFQ2 AFQ11 AFQ12 AFQ22 ACOHORT_BSIZE_BFQ1 BFQ2 BFQ11 BFQ12 BFQ22 B
29AGHELD_FEM_BAD8010060323612HELD_FEM_GOOD788076194217
160TCHELD_MAL_ADRCASE3ULN161319376HELD_MAL_ADRCTRL59724622289
194GCHELD_FEM_ADRCASE5ULN141018347HELD_FEM_ADRCTRL647553213310
194GCHELD_ALL_ADRCASE5ULN201822668HELD_ALL_ADRCTRL123145101406518
194GCHELD_FEM_HIRESP2492902088112840HELD_FEM_LORESP2612742488011467
411ATHELD_ALL_ADRCASE5ULN2625276137HELD_ALL_ADRCTRL12615894496017
466CTHELD_FEM_ADRCASE716181104120HELD_FEM_ADRCTRL697563242718
466CTHELD_MAL_ADRCASE5ULN9144540HELD_MAL_ADRCTRL565854172415
555AGHELD_ALL_BAD9712965453913HELD_ALL_GOOD11513595356515
623CTHELD_MAL_ADRCASE3ULN163201600HELD_MAL_ADRCTRL5911085261
625CTHELD_FEM_ADRCASE3ULN3129336178HELD_FEM_ADRCTRL63824427288
777CTHELD_ALL_BAD1021624265325HELD_ALL_GOOD1101942686222
777CTHELD_ALL_LOHDL2437111491HELD_ALL_HIHDL325952750
777CTHELD_ALL_CASE2731281856161HELD_ALL_CTRL253822434145
777CTHELD_FEM_CASE2376682980HELD_FEM_CTRL23045151893
777CTHELD_FEM_BAD841333553274HELD_FEM_GOOD751321858161
777CTHELD_ALL_BAD981573964295HELD_ALL_GOOD1141992987252
1005AGHELD_FEM_BAD841422659241HELD_FEM_GOOD74136126482
1062GAHELD_ALL_BAD2625108416647413615HELD_ALL_GOOD2714120921950719512
1275CGCVD_FEM_CASE3019416717CVD_FEM_CTRL14208761
1275CGHELD_MAL_CASE241582418221HELD_MAL_CTRL22828286166
1275CGHELD_MAL_LOHDL182412882HELD_MAL_HIHDL2420284128
1275CGCVD_MAL_CASE515844211614CVD_MAL_CTRL2030101424
1669TCHELD_MAL_CASE2417843740HELD_MAL_CTRL22845111891
1669TCHELD_ALL_CASE2971722276201HELD_ALL_CTRL2671043040243
1669TCCVD_ALL_CASE961623072186CVD_ALL_CTRL741202847261
1669TCHELD_MAL_CASE142711310HELD_MAL_CTRL182971251
1755AGHELD_MAL_BAD230638722514310162HELD_MAL_GOOD234541327713414566
1765AGHELD_FEM_BAD862115141369HELD_FEM_GOOD702711322345
2109AGHELD_FEM_BAD23165211112178712HELD_FEM_GOOD235956115722211720
2150TCHELD_ALL_BAD981564065267HELD_ALL_GOOD1151913976390
2150TCHELD_ALL_BAD1021624267287HELD_ALL_GOOD1111853774370
2150TCHELD_MAL_BAD192991333HELD_MAL_GOOD36621026100
2150TCHELD_MAL_BAD192991333HELD_MAL_GOOD36621026100
2150TCHELD_FEM_BAD791273152234HELD_FEM_GOOD791292950290
2234TGHELD_ALL_BAD1001366442526HELD_ALL_GOOD10914177494317
2321GTHELD_MAL_BAD183061260HELD_MAL_GOOD356733230
2321GTHELD_MAL_BAD183061260HELD_MAL_GOOD356733230
2321GTHELD_FEM_BAD8015467460HELD_FEM_GOOD791431565131
2354CTCVD_FEM_CASE35571322130CVD_FEM_CTRL407643640
3451CTHELD_FEM_ADRCASE736482114220HELD_FEM_ADRCTRL697464232818
3451CTHELD_MAL_ADRCASE5ULN9144540HELD_MAL_ADRCTRL606258182616
3452AGHELD_MAL_ADRCASE5ULN9171810HELD_MAL_ADRCTRL60833729256
3453CTHELD_FEM_ADRCASE711033936314HELD_FEM_ADRCTRL698454263211
4912GAHELD_FEM_BAD707862341026HELD_FEM_GOOD60516923532
5093GACVD_FEM_CASE32303491211CVD_FEM_CTRL39522618165
5093GAHELD_MAL_CASE11166641HELD_MAL_CTRL171420386
6333ACHELD_MAL_ADRCASE5ULN888080HELD_MAL_ADRCTRL546147192312
6333ACHELD_ALL_ADRCASE124114134256435HELD_ALL_ADRCTRL11713698444825
6333ACHELD_ALL_ADRCASE3ULN44375162513HELD_ALL_ADRCTRL11713698444825
6333ACHELD_FEM_ADRCASE3ULN28223441410HELD_FEM_ADRCTRL637551252513
6333ACHELD_ALL_ADRCASE5ULN2422263165HELD_ALL_ADRCTRL11713698444825
6333ACHELD_MAL_ADRCASE57496583316HELD_MAL_ADRCTRL546147192312
6333ACCVD_MAL_CASE3237278213CVD_MAL_CTRL32293581311
7407GAHELD_ALL_ADRCASE5ULN879233HELD_ALL_ADRCTRL50326813019
7407GAHELD_FEM_ADRCASE5ULN777232HELD_FEM_ADRCTRL2314320149
7407GAHELD_FEM_ADRCASE2726284185HELD_FEM_ADRCTRL2314320149
7407GAHELD_FEM_ADRCASE3ULN131313373HELD_FEM_ADRCTRL2314320149
10584GTHELD_ALL_ADRCASE13325412121120HELD_ALL_ADRCTRL130257312730
10584GTHELD_FEM_ADRCASE7013376370HELD_FEM_ADRCTRL7013916910
10584GTHELD_FEM_ADRCASE3ULN295532630HELD_FEM_ADRCTRL7013916910
11021TCHELD_FEM_BAD801332755232HELD_FEM_GOOD711291359111
11062TCHELD_MAL_ADRCASE5ULN8142620HELD_MAL_ADRCTRL58754122315
11147CTHELD_FEM_ADRCASE60754519374HELD_FEM_ADRCTRL565953162713
11212GCHELD_ALL_LOHDL10146541HELD_ALL_HIHDL151218285
11371AGHELD_ALL_ADRCASE3ULN488974170HELD_ALL_ADRCTRL129252612360
11371AGHELD_FEM_ADRCASE7313886580HELD_FEM_ADRCTRL7114026920
11487TAHELD_FEM_UHIRESP52743027205HELD_FEM_ULORESP721162844280
11585GTHELD_ALL_BAD10411791286115HELD_ALL_GOOD110104116255431
11683CGHELD_FEM_UHIRESP56813128253HELD_FEM_ULORESP781282855185
11863GAHELD_FEM_VHIRESP15428820134200HELD_FEM_VLORESP15026436115341
12024CTHELD_ALL_ADRCASE13425513121130HELD_ALL_ADRCTRL131259312830
12024CTHELD_FEM_ADRCASE3ULN295442540HELD_FEM_ADRCTRL7114117010
12024CTHELD_FEM_ADRCASE7113486380HELD_FEM_ADRCTRL7114117010
12024CTHELD_ALL_ADRCASE3ULN468754150HELD_ALL_ADRCTRL131259312830
12632CTHELD_MAL_ADRCASE5ULN9171810HELD_MAL_ADRCTRL6412806400
13994GACVD_FEM_CASE305642802CVD_FEM_CTRL377403700
13994GAHELD_MAL_ADRCASE5210405200HELD_MAL_ADRCTRL509734811
14090CAHELD_FEM_HIRESP26945583191735HELD_FEM_LORESP27548763219497
14159TCHELD_FEM_HIRESP29236521912012547HELD_FEM_LORESP2933432439415544
14362TGHELD_FEM_UHIRESP5710955250HELD_FEM_ULORESP791401863142
14410GAHELD_MAL_ADRCASE6112025920HELD_MAL_ADRCTRL6311885580
14488AGHELD_ALL_ADRCASE13225212120120HELD_ALL_ADRCTRL131259312830
14488AGHELD_FEM_ADRCASE7113576470HELD_FEM_ADRCTRL7114117010
14488AGHELD_FEM_ADRCASE3ULN305732730HELD_FEM_ADRCTRL7114117010
14490CTHELD_MAL_ADRCASE5ULN9180900HELD_MAL_ADRCTRL58912536193
14490CTHELD_FEM_ADRCASE5ULN172311791HELD_FEM_ADRCTRL711212151191
14490CTHELD_FEM_ADRCASE3ULN31451715151HELD_FEM_ADRCTRL711212151191
14493AGHELD_ALL_ADRCASE13525713122130HELD_ALL_ADRCTRL128253312530
14493AGHELD_FEM_ADRCASE7313886580HELD_FEM_ADRCTRL6913716810
14493AGHELD_FEM_ADRCASE3ULN315842740HELD_FEM_ADRCTRL6913716810
14493AGHELD_ALL_ADRCASE3ULN489154350HELD_ALL_ADRCTRL128253312530
14554CAHELD_MAL_ADRCASE3ULN163201600HELD_MAL_ADRCTRL61992349111
14554CAHELD_MAL_ADRCASE5ULN8160800HELD_MAL_ADRCTRL61992349111
14554CAHELD_MAL_ADRCASE61110125506HELD_MAL_ADRCTRL61992349111
14603AGCVD_MAL_CASE396993090CVD_MAL_CTRL122401200
14820AGHELD_FEM_VHIRESP14719797656715HELD_FEM_VLORESP14218797714526
14820AGHELD_FEM_UHIRESP55743624265HELD_FEM_ULORESP769656372217
14876CTHELD_FEM_HIRESP28034022011111851HELD_FEM_LORESP2853442269615237
14876CTHELD_FEM_VHIRESP147179115605928HELD_FEM_VLORESP145166124438022
14954GCHELD_MAL_ADRCASE5911805900HELD_MAL_ADRCTRL6512736311
14957ACHELD_FEM_ADRCASE5ULN173401700HELD_FEM_ADRCTRL781451167110
14957ACHELD_FEM_VHIRESP14826531118291HELD_FEM_VLORESP14326917127151
14977AGHELD_FEM_UHIRESP56763629189HELD_FEM_ULORESP751183245282
15349CTHELD_MAL_ADRCASE59813727275HELD_MAL_ADRCTRL657258203213
15590GAHELD_ALL_ADRCASE5ULN2533179151HELD_ALL_ADRCTRL140149131446135
15590GAHELD_ALL_ADRCASE130149111377518HELD_ALL_ADRCTRL140149131446135
15590GAHELD_FEM_ADRCASE718161204110HELD_FEM_ADRCTRL767874243022
16268CGHELD_MAL_ADRCASE5ULN9180900HELD_MAL_ADRCTRL651121848161
36078AGHELD_FEM_VHIRESP224131930HELD_FEM_VLORESP17268980
36078AGHELD_FEM_HIRESP325952750HELD_FEM_LORESP26421016100
36406TCHELD_FEM_ADRCASE5ULN172771070HELD_FEM_ADRCTRL748365233714
37135CTHELD_ALL_ADRCASE3ULN445038191213HELD_ALL_ADRCTRL11713599376119
37135CTHELD_FEM_ADRCASE3ULN29322613610HELD_FEM_ADRCTRL616755183112
37135CTHELD_FEM_ADRCASE5ULN172113935HELD_FEM_ADRCTRL616755183112
37135CTHELD_ALL_ADRCASE5ULN2430181266HELD_ALL_ADRCTRL11713599376119
37327TCHELD_ALL_CASE2172014764HELD_ALL_CTRL2360300
37327TCHELD_FEM_VHIRESP14320680804617HELD_FEM_VLORESP12716391516115
37327TCHELD_FEM_UHIRESP53832333173HELD_FEM_ULORESP69904828347
37327TCHELD_MAL_ADRCASE55872343111HELD_MAL_ADRCTRL49643431216
37404TCHELD_MAL_ADRCASE499444621HELD_MAL_ADRCTRL499804900
37413ATHELD_FEM_ADRCASE5ULN172311791HELD_FEM_ADRCTRL611071546150
37413ATHELD_FEM_ADRCASE3ULN30431714151HELD_FEM_ADRCTRL611071546150
37413ATHELD_ALL_ADRCASE5ULN24361213101HELD_ALL_ADRCTRL1172062890261
37413ATHELD_ALL_ADRCASE3ULN45702026181HELD_ALL_ADRCTRL1172062890261
37939CTHELD_FEM_HIRESP29554446254365HELD_FEM_LORESP29855145253450
37939CTCVD_MAL_CASE36601225101CVD_MAL_CTRL132421201
38009TGHELD_ALL_ADRCASE1262203296282HELD_ALL_ADRCTRL1161844875347
38009TGHELD_MAL_ADRCASE571011344130HELD_MAL_ADRCTRL55882237144
40004GCCVD_FEM_CASE172311872CVD_FEM_CTRL162931330
40522TAHELD_FEM_ADRCASE731123445226HELD_FEM_ADRCTRL7810056343212
40522TAHELD_FEM_ADRCASE3ULN31491319111HELD_FEM_ADRCTRL7810056343212
40522TAHELD_FEM_ADRCASE5ULN172861160HELD_FEM_ADRCTRL7810056343212
41847TGHELD_FEM_HIRESP2222661787910835HELD_FEM_LORESP223229217679561
42084ACHELD_MAL_ADRCASE5ULN7113511HELD_MAL_ADRCTRL561001244120
42084ACHELD_FEM_ADRCASE3ULN31481417140HELD_FEM_ADRCTRL621081648122
42084ACHELD_FEM_ADRCASE711162645260HELD_FEM_ADRCTRL621081648122
42084ACHELD_ALL_ADRCASE5ULN25381214101HELD_ALL_ADRCTRL1182082892242
42084ACHELD_FEM_ADRCASE5ULN18279990HELD_FEM_ADRCTRL621081648122
42084ACHELD_ALL_ADRCASE3ULN46731928171HELD_ALL_ADRCTRL1182082892242
42677CGHELD_FEM_ADRCASE3ULN30411913152HELD_FEM_ADRCTRL596157153113
42677CGHELD_FEM_ADRCASE5ULN172410881HELD_FEM_ADRCTRL596157153113
42677CGHELD_FEM_ADRCASE68874925376HELD_FEM_ADRCTRL596157153113
46865TCHELD_FEM_VHIRESP15124854101464HELD_FEM_VLORESP1432068072629
46865TCHELD_FEM_HIRESP272439105176879HELD_FEM_LORESP27641613615510615
46865TCHELD_ALL_ADRCASE5ULN26371511150HELD_ALL_ADRCTRL13620369774910
47856TCHELD_ALL_ADRCASE5ULN264392033HELD_ALL_ADRCTRL14321472815210
47856TCHELD_MAL_ADRCASE5ULN9171810HELD_MAL_ADRCTRL65983236263
47856TCHELD_FEM_VHIRESP15322284806211HELD_FEM_VLORESP1512406297468
48490AGCVD_ALL_CASE46533916219CVD_ALL_CTRL35234741516
48490AGCVD_MAL_CASE30372312135CVD_MAL_CTRL171222287
48490AGHELD_ALL_ADRCASE3ULN47415362912HELD_ALL_ADRCTRL135151119446328
48490AGHELD_FEM_ADRCASE3ULN3025353198HELD_FEM_ADRCTRL728361253314
48490AGHELD_FEM_ADRCASE706377133720HELD_FEM_ADRCTRL728361253314
50164GAHELD_FEM_ADRCASE3ULN31501220101HELD_FEM_ADRCTRL77143116791
50164GAHELD_FEM_ADRCASE751272353211HELD_FEM_ADRCTRL77143116791
50164GAHELD_ALL_ADRCASE5ULN2641111772HELD_ALL_ADRCTRL14225232112282
54704GAHELD_FEM_ADRCASE681251157110HELD_FEM_ADRCTRL6011825820
54806GACVD_ALL_CASE346443040CVD_ALL_CTRL316203100
54806GAHELD_FEM_UHIRESP539974751HELD_FEM_ULORESP731281855180
54807GAHELD_FEM_ADRCASE5ULN172212782HELD_FEM_ADRCTRL701241656122
54807GAHELD_ALL_ADRCASE5ULN26351712113HELD_ALL_ADRCTRL1292184093324
54807GAHELD_FEM_ADRCASE711073540274HELD_FEM_ADRCTRL701241656122
54807GAHELD_ALL_ADRCASE1342056377516HELD_ALL_ADRCTRL1292184093324
54807GAHELD_FEM_ADRCASE3ULN31471518112HELD_FEM_ADRCTRL701241656122
54807GAHELD_FEM_HIRESP281461101189839HELD_FEM_LORESP2674111231609116
54807GAHELD_ALL_ADRCASE3ULN48722427183HELD_ALL_ADRCTRL1292184093324
54807GAHELD_FEM_UHIRESP53941241120HELD_FEM_ULORESP691092943233
55733GACVD_MAL_CASE3458102581CVD_MAL_CTRL132601300
55733GACVD_FEM_CASE153001500CVD_FEM_CTRL162841240
55733GAHELD_FEM_VHIRESP15528921134210HELD_FEM_VLORESP15026535116331
55733GAHELD_ALL_ADRCASE13625220117181HELD_ALL_ADRCTRL14024535107312
55846AGHELD_FEM_VHIRESP136169103555922HELD_FEM_VLORESP14420781765513
55846AGHELD_FEM_UHIRESP526242212011HELD_FEM_ULORESP761114142277
55906GTHELD_FEM_HIRESP26411115110HELD_FEM_LORESP515745172311
56084CTHELD_FEM_UHIRESP888161HELD_FEM_ULORESP223681642
57818GAHELD_MAL_ADRCASE631002640203HELD_MAL_ADRCTRL6512375951
57818GAHELD_ALL_ADRCASE1382294796375HELD_ALL_ADRCTRL14226222121201
57818GAHELD_MAL_ADRCASE3ULN172771232HELD_MAL_ADRCTRL6512375951
57818GAHELD_ALL_ADRCASE3ULN48801635103HELD_ALL_ADRCTRL14226222121201
57818GAHELD_FEM_HIRESP29150973223635HELD_FEM_LORESP29353551245453
57819TCHELD_MAL_ADRCASE61932935233HELD_MAL_ADRCTRL651161453102
57819TCHELD_ALL_ADRCASE1362155786437HELD_ALL_ADRCTRL14324937111275
57819TCHELD_FEM_HIRESP28948494200845HELD_FEM_LORESP28950672224587
57828AGHELD_FEM_VHIRESP149175123556529HELD_FEM_VLORESP148179117468715
57987TCHELD_MAL_ADRCASE5ULN9108180HELD_MAL_ADRCTRL657159193313
59456ACHELD_MAL_ADRCASE3ULN15237951HELD_MAL_ADRCTRL56644817309
59460TCHELD_FEM_UHIRESP53772924290HELD_FEM_ULORESP771005430407
59461CTHELD_MAL_ADRCASE5ULN9162801HELD_MAL_ADRCTRL648345302311
59461CTHELD_FEM_UHIRESP53802627260HELD_FEM_ULORESP771045034367
59461CTHELD_FEM_HIRESP28040615414711221HELD_FEM_LORESP28237818612912033
60900AGHELD_FEM_ADRCASE3ULN3037238211HELD_FEM_ADRCTRL56753726237
60900AGHELD_MAL_ADRCASE51643819266HELD_MAL_ADRCTRL47722228163
60900AGHELD_ALL_ADRCASE3ULN43563015262HELD_ALL_ADRCTRL10314759543910
60902ATHELD_MAL_ADRCASE53871936152HELD_MAL_ADRCTRL53723425226
60902ATHELD_ALL_ADRCASE1141814772375HELD_ALL_ADRCTRL11215965584311
60934CTCVD_ALL_CASE52752929176CVD_ALL_CTRL32303481410
60934CTCVD_MAL_CASE36522020124CVD_MAL_CTRL131214364
60934CTHELD_MAL_ADRCASE627549262313HELD_MAL_ADRCTRL63893729313
60934CTCVD_FEM_CASE16239952CVD_FEM_CTRL191820586
60957GAHELD_MAL_ADRCASE5ULN8160800HELD_MAL_ADRCTRL56892335192
60957GAHELD_MAL_ADRCASE3ULN163021420HELD_MAL_ADRCTRL56892335192
60959TCHELD_MAL_ADRCASE3ULN151119195HELD_MAL_ADRCTRL55723822285
60959TCHELD_MAL_ADRCASE5ULN8610062HELD_MAL_ADRCTRL55723822285
60959TCHELD_ALL_ADRCASE3ULN45424892412HELD_ALL_ADRCTRL11514090425617
60959TCHELD_ALL_ADRCASE126130122356031HELD_ALL_ADRCTRL11514090425617
60959TCHELD_MAL_ADRCASE586155182515HELD_MAL_ADRCTRL55723822285
60962CTHELD_MAL_ADRCASE5ULN435112HELD_MAL_ADRCTRL40651527112
60962CTHELD_MAL_ADRCASE3ULN999252HELD_MAL_ADRCTRL40651527112
60962CTHELD_MAL_ADRCASE36482417145HELD_MAL_ADRCTRL40651527112
60974GAHELD_FEM_ADRCASE5ULN172771232HELD_FEM_ADRCTRL751212947271
60978GCHELD_MAL_ADRCASE6312336030HELD_MAL_ADRCTRL651171353111
60978GCHELD_FEM_HIRESP29454642255363HELD_FEM_LORESP29754450247500
60978GCHELD_FEM_VHIRESP15929424137202HELD_FEM_VLORESP15127131120310
60999GTHELD_MAL_ADRCASE5ULN9180900HELD_MAL_ADRCTRL641141450140
61011TCCVD_MAL_CASE38621424140CVD_MAL_CTRL132421201
61011TCHELD_FEM_HIRESP2894721061968013HELD_FEM_LORESP28447791196853
61086GAHELD_MAL_ADRCASE397173270HELD_MAL_ADRCTRL36561622122
61126CTHELD_MAL_ADRCASE596850232214HELD_MAL_ADRCTRL56674516355
61126CTHELD_FEM_VHIRESP152152152338633HELD_FEM_VLORESP137165109516323
61126CTHELD_FEM_UHIRESP545454103410HELD_FEM_ULORESP728856293013
61126CTHELD_FEM_HIRESP2742922567614058HELD_FEM_LORESP2663172159812147
61137TCHELD_ALL_ADRCASE1332115581493HELD_ALL_ADRCTRL14024139103352
61147GAHELD_FEM_HIRESP29333525110113359HELD_FEM_LORESP29636322910515338
61176AGHELD_MAL_ADRCASE5ULN8142620HELD_MAL_ADRCTRL55634716318
61176AGHELD_MAL_ADRCASE56803230206HELD_MAL_ADRCTRL55634716318
61176AGHELD_MAL_ADRCASE3ULN162481042HELD_MAL_ADRCTRL55634716318
61176AGHELD_ALL_ADRCASE5ULN2638141664HELD_ALL_ADRCTRL11715084465813
61184CTHELD_MAL_ADRCASE5ULN9162801HELD_MAL_ADRCTRL61962638203
61184CTHELD_MAL_ADRCASE611081449102HELD_MAL_ADRCTRL61962638203
61197AGHELD_MAL_ADRCASE3ULN1724101043HELD_MAL_ADRCTRL631091747151
61270AGHELD_MAL_ADRCASE3ULN16239790HELD_MAL_ADRCTRL5510194690
61270AGHELD_MAL_ADRCASE5ULN8115350HELD_MAL_ADRCTRL5510194690
61270AGHELD_ALL_CASE2173221520HELD_ALL_CTRL2342120
61272AGHELD_MAL_ADRCASE5ULN8106341HELD_MAL_ADRCTRL56892333230
61272AGHELD_FEM_ADRCASE691162250163HELD_FEM_ADRCTRL62913332273
61284GAHELD_FEM_HIRESP29032925110412165HELD_FEM_LORESP29535823210315240
61292GAHELD_FEM_HIRESP28833324310013355HELD_FEM_LORESP29438120711814531
61292GAHELD_MAL_ADRCASE62784621365HELD_MAL_ADRCTRL648345302311
61297TCCVD_ALL_CASE9213450532811CVD_ALL_CTRL641062246144
61324GAHELD_FEM_VHIRESP2129131254HELD_FEM_VLORESP171519557
61328AGHELD_FEM_HIRESP277551327511HELD_FEM_LORESP276552027600
61373GCHELD_FEM_ADRCASE751361461140HELD_FEM_ADRCTRL761223050224
61373GCHELD_ALL_ADRCASE13624428110242HELD_ALL_ADRCTRL14123646100365
900066CTHELD_MAL_BAD173041502HELD_MAL_GOOD3253112372
900071GCHELD_FEM_UHIRESP52574713318HELD_FEM_ULORESP776688173228
900072GCHELD_FEM_UHIRESP41503216187HELD_FEM_ULORESP625371142523
900072GCHELD_FEM_LOHDL2520302167HELD_FEM_HIHDL2728269108
900072GCHELD_FEM_VHIRESP123141105445326HELD_FEM_VLORESP115111119305134
900073GCHELD_ALL_ADRCASE12515892456812HELD_ALL_ADRCTRL1211786464507
900073GCHELD_MAL_ADRCASE59714717375HELD_MAL_ADRCTRL55822830223
900073GCHELD_ALL_CASE2264571970HELD_ALL_CTRL2222020
900073GCHELD_MAL_ADRCASE3ULN171915593HELD_MAL_ADRCTRL55822830223
900073GCHELD_FEM_HIRESP29539819213213429HELD_FEM_LORESP29943516315811922
900074CTHELD_FEM_BAD768567194710HELD_FEM_GOOD69934529355
900074CTHELD_FEM_UHIRESP52703423245HELD_FEM_ULORESP798771253717
900083AGHELD_FEM_HIRESP2812962668113466HELD_FEM_LORESP28032923110012951
900115AGHELD_MAL_ADRCASE3ULN161319457HELD_MAL_ADRCTRL59744422307
900115AGHELD_ALL_CASE45543615246HELD_ALL_CTRL40611924133
900115AGHELD_ALL_ADRCASE5ULN2525257117HELD_ALL_ADRCTRL13016991536314
900143GTHELD_MAL_ADRCASE5ULN777070HELD_MAL_ADRCTRL535947182312
900143GTHELD_ALL_ADRCASE122112132256235HELD_ALL_ADRCTRL11713797435123
900143GTHELD_FEM_ADRCASE3ULN29233541510HELD_FEM_ADRCTRL647850252811
900143GTHELD_ALL_ADRCASE3ULN43365062413HELD_ALL_ADRCTRL11713797435123
900143GTHELD_ALL_ADRCASE5ULN2422263165HELD_ALL_ADRCTRL11713797435123
900143GTHELD_FEM_ADRCASE676569173119HELD_FEM_ADRCTRL647850252811
900173TGHELD_MAL_ADRCASE3ULN163021420HELD_MAL_ADRCTRL55832731213
900174AGHELD_MAL_ADRCASE3ULN161220367HELD_MAL_ADRCTRL54713722275
900174AGHELD_MAL_ADRCASE5ULN8511134HELD_MAL_ADRCTRL54713722275
900174AGHELD_ALL_ADRCASE5ULN222123697HELD_ALL_ADRCTRL11314878485213
900174AGHELD_FEM_CASE2831257174HELD_FEM_CTRL2132101362
900174AGHELD_ALL_CASE42493513236HELD_ALL_CTRL37551921133
900175GAHELD_FEM_HIRESP12213930HELD_FEM_LORESP2229159112
900180GACVD_ALL_CASE10269135124545CVD_ALL_CTRL737670213418
900180GACVD_FEM_CASE33184821417CVD_FEM_CTRL404436141610
900180GAHELD_MAL_CASE141018266HELD_MAL_CTRL182610981
900180GAHELD_ALL_CASE44335571918HELD_ALL_CTRL40483213225
900221GCHELD_MAL_ADRCASE54684020286HELD_MAL_ADRCTRL525153142315
900250CTHELD_MAL_ADRCASE5ULN9126522HELD_MAL_ADRCTRL591031545131
900342GAHELD_ALL_ADRCASE1131804671384HELD_ALL_ADRCTRL1131992789213
900342GAHELD_FEM_ADRCASE62962837223HELD_FEM_ADRCTRL611081449102
900344ACHELD_FEM_ADRCASE706278153223HELD_FEM_ADRCTRL729351322911
900344ACHELD_FEM_ADRCASE3ULN34303881412HELD_FEM_ADR3CTRL729351322911
900344ACHELD_ALL_ADRCASE128127129345935HELD_ALL_ADRCTRL12715599495721
900344ACHELD_FEM_ADRCASE5ULN191721496HELD_FEM_ADR5CTRL729351322911
10000001GAHELD_MAL_BAD172410962HELD_MAL_GOOD3637355274
10000001GAHELD_ALL_BAD10012674365410HELD_ALL_GOOD110110110246224
10000002AGHELD_ALL_BAD1021584664308HELD_ALL_GOOD10914672504613
10000017TCHELD_ALL_BAD1021772776251HELD_ALL_GOOD1102011994133

TABLE 5b
p-values of PA SNPs.
A SNP is considered as associated to cardiovascular disease, adverse statin response or to efficacy
of statin treatment, respectively, when one of the p values is equal or below 0.05.
GTYPEGTYPEGTYPEALLELEALLELEALLELE
BAYSNPCOMPARISONCPVALXPVALLRPVALCPVALXPVALLRPVAL
160HELD_MAL_ADR3ULN0.10810.11250.12330.0390.04570.0396
194HELD_FEM_ADR5ULN0.01840.01970.0310.02770.0360.0275
194HELD_ALL_ADR5ULN0.0190.02030.03180.09850.12120.1003
194HELD_FEM_EFF0.02530.02540.02450.06520.0680.0651
411HELD_ALL_ADR5ULN0.13690.13830.14830.04990.06160.052
466HELD_FEM_ADR0.01270.01220.01160.05660.07270.0563
466HELD_MAL_ADR5ULN0.14440.13430.05690.03950.04430.0336
555HELD_ALL_LIP0.04050.04040.040.09880.10810.0982
623HELD_MAL_ADR3ULN0.3510.47250.16950.13010.20310.0466
625HELD_FEM_ADR3ULN0.05410.05710.04840.01640.01860.0168
777HELD_ALL_LIP0.0560.05270.05450.01390.01690.0137
777HELD_ALL_HDL0.07320.0430.0610.02380.03020.0239
777HELD_ALL_CC20.07680.08150.0710.03010.03940.0312
777HELD_FEM_CC20.08390.07470.04770.03030.03850.0302
777HELD_FEM_LIP0.1140.12370.1060.03490.04940.0332
777HELD_ALL_LIP0.14230.13810.13990.04460.04740.0448
1005HELD_FEM_LIP0.01890.01240.01590.04450.05610.0418
1062HELD_ALL_LIP20.0480.050.04740.13030.13630.1296
1275CVD_FEM0.00720.00550.00330.00050.00060.0004
1275HELD_MAL_CC20.01520.01040.01270.01360.01970.0138
1275HELD_MAL_HDL0.0830.09590.07580.02320.02860.0222
1275CVD_MAL0.06980.07840.05820.04520.05520.0411
1669HELD_MAL_CC20.0260.01640.02240.00620.01030.0064
1669HELD_ALL_CC20.02610.02030.02660.00710.00880.0076
1669CVD_ALL0.02290.02180.01960.42340.46830.4246
1669HELD_MAL_CC0.19620.19590.14690.05680.12360.0421
1755HELD_MAL_LIP20.05050.04940.050.2110.2310.2108
1765HELD_FEM_LIP0.03130.02710.03110.08490.1140.0857
2109HELD_FEM_LIP20.15380.15430.15220.0480.05540.0474
2150HELD_ALL_LIP0.01030.00770.00270.36090.3830.3616
2150HELD_ALL_LIP0.01630.01370.00430.29820.31980.2984
2150HELD_MAL_LIP0.03940.04610.02720.19620.28820.204
2150HELD_MAL_LIP0.03940.04610.02720.19620.28820.204
2150HELD_FEM_LIP0.09390.10070.04330.77420.88610.7742
2234HELD_ALL_LIP0.04340.04250.0390.47310.53450.4729
2321HELD_MAL_LIP0.0230.0480.02680.03030.05910.036
2321HELD_MAL_LIP0.0230.0480.02680.03030.05910.036
2321HELD_FEM_LIP0.12520.06910.10010.03920.04390.0364
2354CVD_FEM0.00510.00630.00440.00890.01030.0078
3451HELD_FEM_ADR0.02970.030.02820.09910.12250.0988
3451HELD_MAL_ADR5ULN0.13980.13530.05530.03780.04410.0321
3452HELD_MAL_ADR5ULN0.07280.06660.04230.02520.04360.0111
3453HELD_FEM_ADR0.08770.08850.08190.03830.04280.038
4912HELD_FEM_LIP0.16020.1560.15830.03360.03540.0334
5093CVD_FEM0.0750.07920.07260.01750.02610.0173
5093HELD_MAL_CC0.08890.09590.08020.02080.0290.0191
6333HELD_MAL_ADR5ULN0.01010.00980.00220.62620.78840.6272
6333HELD_ALL_ADR0.01120.01150.01080.00760.00830.0075
6333HELD_ALL_ADR3ULN0.01370.01270.00860.00990.01210.0099
6333HELD_FEM_ADR3ULN0.04620.04590.03590.01150.01550.0114
6333HELD_ALL_ADR5ULN0.03590.03390.02560.11820.15050.1196
6333HELD_MAL_ADR0.0340.03610.03170.04440.05990.044
6333CVD_MAL0.03970.04220.0340.15710.21560.1566
7407HELD_ALL_ADR5ULN0.02160.03580.07860.35560.39870.3637
7407HELD_FEM_ADR5ULN0.02960.05270.04240.1790.21110.1857
7407HELD_FEM_ADR0.06870.08470.0320.07150.10110.07
7407HELD_FEM_ADR3ULN0.04930.06820.03230.09950.13030.1012
10584HELD_ALL_ADR0.01890.03040.01520.02070.03280.0167
10584HELD_FEM_ADR0.02890.06250.02090.03140.06640.0227
10584HELD_FEM_ADR3ULN0.04030.07430.05330.04240.07640.0562
11021HELD_FEM_LIP0.12320.11850.11820.04820.06090.0457
11062HELD_MAL_ADR5ULN0.12840.15720.1020.06760.08880.0493
11147HELD_FEM_ADR0.03970.03790.0350.13020.14470.13
11212HELD_ALL_HDL0.10730.11390.10070.03750.04750.0355
11371HELD_ALL_ADR3ULN0.02430.04550.03390.02720.04960.0381
11371HELD_FEM_ADR0.05470.09740.0470.05920.10360.0508
11487HELD_FEM_UEFF0.02510.0220.01040.08430.09550.0859
11585HELD_ALL_LIP0.04980.0530.04710.06320.06670.063
11683HELD_FEM_UEFF0.03020.0310.03070.0580.07260.0593
11863HELD_FEM_VEFF0.04910.02950.03960.01890.02420.0182
12024HELD_ALL_ADR0.01130.01770.00860.01270.01950.0096
12024HELD_FEM_ADR3ULN0.00990.0240.01490.01090.02560.0165
12024HELD_FEM_ADR0.01590.03320.01040.01770.03610.0116
12024HELD_ALL_ADR3ULN0.0160.02890.02590.01720.03050.0281
12632HELD_MAL_ADR5ULN0.00730.12330.03840.00750.12330.0396
13994CVD_FEM0.11080.19670.06970.02410.0380.0103
13994HELD_MAL_ADR0.34620.23780.23530.07520.1160.0376
14090HELD_FEM_EFF0.03170.02930.03120.05460.06170.0543
14159HELD_FEM_EFF0.03940.040.03910.16510.16940.165
14362HELD_FEM_UEFF0.14530.14010.09580.04040.04720.0335
14410HELD_MAL_ADR0.05410.09560.04650.05940.10270.051
14488HELD_ALL_ADR0.01740.03020.0140.01910.03270.0154
14488HELD_FEM_ADR0.0290.06260.0210.03140.06650.0227
14488HELD_FEM_ADR3ULN0.04310.07730.05590.04520.07940.0588
14490HELD_MAL_ADR5ULN0.07880.08990.01990.0290.04440.0045
14490HELD_FEM_ADR5ULN0.04690.05950.05720.01710.0250.0241
14490HELD_FEM_ADR3ULN0.07340.08090.07790.03310.04920.0377
14493HELD_ALL_ADR0.01350.01830.01030.0150.02010.0114
14493HELD_FEM_ADR0.02010.03390.01310.02220.03680.0145
14493HELD_FEM_ADR3ULN0.01510.03110.020.01640.03290.0219
14493HELD_ALL_ADR3ULN0.0220.03570.03270.02360.03750.0352
14554HELD_MAL_ADR3ULN0.1550.29230.04620.00770.00940.0006
14554HELD_MAL_ADR5ULN0.38580.41350.19490.05710.07330.0125
14554HELD_MAL_ADR0.24450.2010.19940.04450.06670.043
14603CVD_MAL0.06670.0940.02020.08140.1110.024
14820HELD_FEM_VEFF0.02410.0240.02330.76750.79190.7675
14820HELD_FEM_UEFF0.03980.04040.03580.4910.51440.4903
14876HELD_FEM_EFF0.02290.02210.02270.90060.90330.9006
14876HELD_FEM_VEFF0.03530.03590.03490.37070.40030.3706
14954HELD_MAL_ADR0.397510.27070.09690.24870.048
14957HELD_FEM_ADR5ULN0.09960.20420.03120.11070.21850.0342
14957HELD_FEM_VEFF0.09530.06750.09170.04710.05090.0455
14977HELD_FEM_UEFF0.02360.02410.0210.04830.06370.0492
15349HELD_MAL_ADR0.09340.09920.08790.03190.03670.0314
15590HELD_ALL_ADR5ULN0.05880.0690.02440.0940.12220.0908
15590HELD_ALL_ADR0.02820.02760.02690.33920.34250.3391
15590HELD_FEM_ADR0.04070.04090.03840.32480.350.3246
16268HELD_MAL_ADR5ULN0.2170.28990.07970.09210.12950.0253
36078HELD_FEM_VEFF0.02140.03290.02050.03550.04990.0347
36078HELD_FEM_EFF0.04820.0710.04760.06830.0950.068
36406HELD_FEM_ADR5ULN0.04130.04810.01360.01210.01860.0093
37135HELD_ALL_ADR3ULN0.01470.01380.01330.88760.89990.8876
37135HELD_FEM_ADR3ULN0.02420.02560.01970.974410.9744
37135HELD_FEM_ADR5ULN0.04870.04890.03820.47650.55920.4746
37135HELD_ALL_ADR5ULN0.05280.0540.04630.5380.63020.5363
37327HELD_ALL_CC20.17120.26320.09580.05120.07430.0167
37327HELD_FEM_VEFF0.0210.02090.02070.05020.05220.0503
37327HELD_FEM_UEFF0.05850.06430.0570.02570.03270.0244
37327HELD_MAL_ADR0.23830.32820.2370.02610.02980.0259
37404HELD_MAL_ADR0.21280.24230.11920.04330.12120.0177
37413HELD_FEM_ADR5ULN0.00930.00590.01320.00550.00910.009
37413HELD_FEM_ADR3ULN0.01430.0110.01360.00750.01210.0092
37413HELD_ALL_ADR5ULN0.05230.05410.07270.01840.02410.027
37413HELD_ALL_ADR3ULN0.05140.05280.05840.01990.02380.0243
37939HELD_FEM_EFF0.05010.04430.01910.87340.91330.8734
37939CVD_MAL0.0890.10750.0260.26230.34190.2367
38009HELD_ALL_ADR0.06290.06230.0580.01810.020.0179
38009HELD_MAL_ADR0.09990.10830.04610.07650.09740.0753
40004CVD_FEM0.09230.08990.06110.02250.0340.0191
40522HELD_FEM_ADR0.07340.07670.07160.01670.01730.0162
40522HELD_FEM_ADR3ULN0.11350.13170.08060.03250.03630.0285
40522HELD_FEM_ADR5ULN0.13240.13590.04830.03970.04440.0317
41847HELD_FEM_EFF0.01190.01250.01140.01010.01040.0101
42084HELD_MAL_ADR5ULN0.01660.1140.09990.24320.37260.2803
42084HELD_FEM_ADR3ULN0.02430.01870.02030.09070.13740.0973
42084HELD_FEM_ADR0.03550.02680.0230.22770.24290.2252
42084HELD_ALL_ADR5ULN0.07360.08840.09120.02460.02870.0344
42084HELD_FEM_ADR5ULN0.02950.06280.03170.07840.11460.0924
42084HELD_ALL_ADR3ULN0.08130.06830.09080.04130.0530.0476
42677HELD_FEM_ADR3ULN0.0890.09950.07370.03390.03810.0323
42677HELD_FEM_ADR5ULN0.13620.15840.11720.05060.07670.0472
42677HELD_FEM_ADR0.08230.08250.07970.04780.05590.0477
46865HELD_FEM_VEFF0.01140.01130.0110.00350.00430.0035
46865HELD_FEM_EFF0.09660.0950.09570.0330.03460.0327
46865HELD_ALL_ADR5ULN0.06970.06220.03490.60.60680.6033
47856HELD_ALL_ADR5ULN0.04350.04570.02660.22150.28920.2077
47856HELD_MAL_ADR5ULN0.1560.14460.10530.06860.07650.0393
47856HELD_FEM_VEFF0.10730.11270.10660.04580.04690.0454
48490CVD_ALL0.01210.01340.010.00180.00240.0016
48490CVD_MAL0.06420.0740.05450.01390.01830.0134
48490HELD_ALL_ADR3ULN0.03160.03390.02140.03950.04220.0395
48490HELD_FEM_ADR3ULN0.03880.03880.02470.03730.04550.0372
48490HELD_FEM_ADR0.08010.08140.07730.03310.04340.0329
50164HELD_FEM_ADR3ULN0.02810.02350.03660.00850.01350.012
50164HELD_FEM_ADR0.04060.02290.03790.02350.02860.0223
50164HELD_ALL_ADR5ULN0.09480.08320.16170.04980.06820.0647
54704HELD_FEM_ADR0.01640.01920.01160.01950.02240.0138
54806CVD_ALL0.04870.1150.01990.05240.12080.0213
54806HELD_FEM_UEFF0.0510.02660.03640.13340.14280.1254
54807HELD_FEM_ADR5ULN0.00520.00810.00850.00070.00160.0017
54807HELD_ALL_ADR5ULN0.01880.02590.02850.00350.00570.0059
54807HELD_FEM_ADR0.01060.00810.00970.00390.00510.0036
54807HELD_ALL_ADR0.04590.04910.0450.02080.02140.0203
54807HELD_FEM_ADR3ULN0.07120.0660.07960.02030.03260.0244
54807HELD_FEM_EFF0.11180.11630.11030.03780.04290.0377
54807HELD_ALL_ADR3ULN0.12440.11330.13340.0390.04420.0442
54807HELD_FEM_UEFF0.10630.11120.06020.04470.0570.0412
55733CVD_MAL0.11910.10980.03670.03860.0570.0085
55733CVD_FEM0.0380.10120.01560.04530.11360.0185
55733HELD_FEM_VEFF0.08710.05220.0710.03640.04880.0357
55733HELD_ALL_ADR0.12420.10430.12130.04350.04720.0422
55846HELD_FEM_VEFF0.06090.05980.05980.01420.01520.0141
55846HELD_FEM_UEFF0.10060.10450.10270.02440.02960.0249
55906HELD_FEM_EFF0.01740.01680.00330.00510.00750.0041
56084HELD_FEM_UEFF0.00860.01090.00710.01370.02140.0171
57818HELD_MAL_ADR0.00110.00060.00080.00030.00030.0002
57818HELD_ALL_ADR0.00510.00370.00430.00080.00120.0007
57818HELD_MAL_ADR3ULN0.05350.04950.09140.00470.01050.0103
57818HELD_ALL_ADR3ULN0.03120.02850.050.01180.01730.0164
57818HELD_FEM_EFF0.1040.12520.10290.03320.03660.0328
57819HELD_MAL_ADR0.01180.00820.01090.00610.00720.0058
57819HELD_ALL_ADR0.03030.02850.02970.01140.01280.0112
57819HELD_FEM_EFF0.03970.03430.03910.0650.0780.0647
57828HELD_FEM_VEFF0.01470.01490.01410.66420.67660.6642
57987HELD_MAL_ADR5ULN0.08920.11140.04140.940110.9401
59456HELD_MAL_ADR3ULN0.1020.10480.10710.05120.05930.0452
59460HELD_FEM_UEFF0.07560.07350.02150.19020.22350.188
59461HELD_MAL_ADR5ULN0.04770.04970.01410.04090.05720.0266
59461HELD_FEM_UEFF0.07570.08540.02160.16660.21160.164
59461HELD_FEM_EFF0.12810.130.12670.04560.05130.0454
60900HELD_FEM_ADR3ULN0.03190.02630.02730.48720.50580.4886
60900HELD_MAL_ADR0.08420.09370.08230.03560.04380.0346
60900HELD_ALL_ADR3ULN0.04080.03530.040.29080.32940.2942
60902HELD_MAL_ADR0.07040.06810.06650.01740.02580.0168
60902HELD_ALL_ADR0.12310.13760.11950.03850.04960.0382
60934CVD_ALL0.01140.010.01030.0010.00170.0011
60934CVD_MAL0.08920.08530.08720.01670.02910.0184
60934HELD_MAL_ADR0.02250.02250.01760.09120.11020.0908
60934CVD_FEM0.16490.19460.15780.03810.05210.0365
60957HELD_MAL_ADR5ULN0.10730.12660.03160.04540.07430.009
60957HELD_MAL_ADR3ULN0.15930.13860.10870.05990.06730.0396
60959HELD_MAL_ADR3ULN0.0110.01190.00820.00440.00620.0047
60959HELD_MAL_ADR5ULN0.06260.07250.01930.03140.05120.0343
60959HELD_ALL_ADR3ULN0.06620.06520.06340.02110.0240.0215
60959HELD_ALL_ADR0.11280.11390.10990.04030.04360.0401
60959HELD_MAL_ADR0.06410.06840.05720.04940.05860.049
60962HELD_MAL_ADR5ULN0.01040.03930.05640.00490.01350.0106
60962HELD_MAL_ADR3ULN0.03040.03030.0340.00530.00870.0084
60962HELD_MAL_ADR0.15580.17580.15170.03980.04320.0394
60974HELD_FEM_ADR5ULN0.04520.0440.07670.867710.8684
60978HELD_MAL_ADR0.05040.03390.0360.01180.01770.009
60978HELD_FEM_EFF0.06750.05210.03760.41340.4480.4131
60978HELD_FEM_VEFF0.07090.04980.04780.23420.25970.2339
60999HELD_MAL_ADR5ULN0.11860.19150.04230.140.21790.0487
61011CVD_MAL0.01180.00840.00240.19410.23160.1671
61011HELD_FEM_EFF0.04160.04270.03260.29840.30950.2982
61086HELD_MAL_ADR0.07980.06250.05380.02450.03960.0232
61126HELD_MAL_ADR0.01490.01440.01350.73550.78930.7355
61126HELD_FEM_VEFF0.01470.01480.01450.01370.01520.0136
61126HELD_FEM_UEFF0.02380.02420.0210.07840.09520.0785
61126HELD_FEM_EFF0.07430.07480.07390.03680.03720.0367
61137HELD_ALL_ADR0.08260.09250.0820.03680.04130.0366
61147HELD_FEM_EFF0.04960.05080.04870.14720.15490.1471
61176HELD_MAL_ADR5ULN0.03530.03510.02890.02050.02660.0129
61176HELD_MAL_ADR0.03160.03120.03020.02760.03530.0273
61176HELD_MAL_ADR3ULN0.04310.03470.04420.070.09840.0639
61176HELD_ALL_ADR5ULN0.04770.04560.04030.21740.25930.2102
61184HELD_MAL_ADR5ULN0.11530.13810.0350.31250.37060.2837
61184HELD_MAL_ADR0.08530.10750.08230.0380.05620.0367
61197HELD_MAL_ADR3ULN0.0250.03560.05610.02780.03850.0369
61270HELD_MAL_ADR3ULN0.00120.00270.00210.00280.00580.0057
61270HELD_MAL_ADR5ULN0.00340.01050.00760.00610.01740.0167
61270HELD_ALL_CC20.02840.08770.04880.03880.09970.0757
61272HELD_MAL_ADR5ULN0.02120.09380.08530.12940.1970.1493
61272HELD_FEM_ADR0.04060.03820.03970.03420.04770.034
61284HELD_FEM_EFF0.00890.00890.00870.16960.17250.1696
61292HELD_FEM_EFF0.01330.01330.01270.01440.0160.0144
61292HELD_MAL_ADR0.03560.03820.03410.74850.79370.7485
61297CVD_ALL0.17240.17190.16560.03950.04150.037
61324HELD_FEM_VEFF0.19050.22080.18480.02860.03680.0281
61328HELD_FEM_EFF0.367910.250.08340.24930.0415
61373HELD_FEM_ADR0.03240.02770.01480.01040.01380.0096
61373HELD_ALL_ADR0.13050.13040.12680.03740.04530.0365
900066HELD_MAL_LIP0.10460.10020.03450.47790.56660.47
900071HELD_FEM_UEFF0.0290.02930.02420.05940.07510.0592
900072HELD_FEM_UEFF0.0560.05920.05080.01040.01530.0102
900072HELD_FEM_HDL0.0540.06190.04490.22580.2440.2251
900072HELD_FEM_VEFF0.17470.17780.17340.04790.05380.0478
900073HELD_ALL_ADR0.02590.02640.02530.01360.01540.0134
900073HELD_MAL_ADR0.02050.02180.01960.0210.02420.0204
900073HELD_ALL_CC20.0330.09520.02720.05520.1170.0977
900073HELD_MAL_ADR3ULN0.10490.09850.11490.03770.05280.0422
900073HELD_FEM_EFF0.12530.12560.12490.04660.04950.0465
900074HELD_FEM_LIP0.0750.07580.07350.04510.05340.0446
900074HELD_FEM_UEFF0.1350.14030.12330.04780.05380.0467
900083HELD_FEM_EFF0.13460.1350.1340.04030.04120.0403
900115HELD_MAL_ADR3ULN0.01470.01520.02590.02480.0280.0255
900115HELD_ALL_CC0.0480.04510.04640.02380.03240.0229
900115HELD_ALL_ADR5ULN0.06190.05670.09140.04470.05530.0475
900143HELD_MAL_ADR5ULN0.0190.01930.00490.68910.77840.6897
900143HELD_ALL_ADR0.01640.01680.01580.00570.00610.0056
900143HELD_FEM_ADR3ULN0.03010.02730.02390.0070.01070.0069
900143HELD_ALL_ADR3ULN0.01920.01920.0130.00790.01110.0079
900143HELD_ALL_ADR5ULN0.0540.06210.0380.10570.11280.1071
900143HELD_FEM_ADR0.15390.16460.15130.04340.04770.0431
900173HELD_MAL_ADR3ULN0.07090.07620.04110.02380.02490.0128
900174HELD_MAL_ADR3ULN0.00490.00460.00950.00430.00710.0045
900174HELD_MAL_ADR5ULN0.00790.01240.02250.00820.01230.009
900174HELD_ALL_ADR5ULN0.04290.0410.06690.02590.02830.0281
900174HELD_FEM_CC0.03230.0330.03040.03320.05440.031
900174HELD_ALL_CC0.06840.0730.06660.03450.04370.0334
900175HELD_FEM_EFF0.13710.20670.09790.05380.08350.0442
900180CVD_ALL0.0040.00380.00380.00060.00070.0006
900180CVD_FEM0.00560.00510.00330.00070.00080.0007
900180HELD_MAL_CC0.01890.02120.01380.00350.00520.0032
900180HELD_ALL_CC0.01010.00770.0080.00360.00530.0034
900221HELD_MAL_ADR0.06820.07490.06380.04110.05250.0408
900342HELD_ALL_ADR0.02920.03390.02810.01520.0210.0147
900342HELD_FEM_ADR0.04140.03730.03910.02060.0270.0196
900344HELD_FEM_ADR0.00520.00530.00470.00060.00080.0006
900344HELD_FEM_ADR3ULN0.0310.03220.03210.00480.00710.005
900344HELD_ALL_ADR0.04410.04470.0430.00950.010.0095
900344HELD_FEM_ADR5ULN0.11090.12220.10780.0260.03930.0275
900250HELD_MAL_ADR5ULN0.01910.05020.08020.02410.03560.0395
10000001HELD_MAL_LIP0.00830.0060.00940.06190.09150.0588
10000001HELD_ALL_LIP0.01610.01660.01480.00730.00790.0072
10000002HELD_ALL_LIP0.04850.04890.04770.01650.01730.0162
10000017HELD_ALL_LIP0.04070.02980.03860.12820.15940.1278

TABLE 6a
Correlation of genotypes of PA SNPs to relative risk
For diagnostic conclusions to be drawn from genotyping a particular
patient we calculated the relative risk RR1, RR2, RR3 for the three
possible genotypes of each SNP. Given the genotype frequencies as
gtype1gtype2gtype3
caseN11N12N13
controlN21N22N23

we calculate RR 1=N 11N 21/N 12+N 13N 22+N 23 RR 2=N 12N 22/N 11+N 13N 21+N 23 RR 3=N 13N 23/N 11+N 12N 21+N 22

Here, the case and control populations represent any case-control-group pair, or bad (case)-good (control)-group pair, respectively (due to their increased response to statins, ‘high responders’ are treated as a case cohort, whereas ‘low responders’ are treated as the respective control cohort). A value RR1>1, RR2>1, and RR3>1 indicates an increased risk for individuals carrying genotype 1, genotype 2, and genotype 3, respectively. For example, RR1=3 indicates a 3-fold risk of an individual carrying genotype 1 as compared to individuals carrying genotype 2 or 3 (a detailed description of relative risk calculation and statistics can be found in (Biostatistics, L. D. Fisher and G. van Belle, Wiley Interscience 1993)). The baySNP number refers to an internal numbering of the PA SNPs and can be found in the sequence listing. null: not defined.

In cases where a relative risk is not given in the table (three times zero or null) the informative genotype can be drawn from the right part of the table where the frequencies of genotypes are given in the cases and control cohorts. For example BaySNP 3360 gave the following results:

BAYSNPCOMPARISONGTYPE1GTYPE2GTYPE3RR1RR2RR3
3360HELD_MAL_ADR5ULNGGGTTTnull00

FQ1_AFQ2_AFQ3_AFQ1_BFQ2_BFQ3_B
100050221

It can be concluded that a GT or TT genotype is only present in the control cohort; these genotypes are somehow protective against ADR. An analogous proceeding can be used to determine protective alleles if no relative risk is given (table 6b).

BAYSNPCOMPARISONGTYPE1GTYPE2GTYPE3RR1RR2
160HELD_MAL_ADR3ULNTTCTCC0.460.89
194HELD_FEM_ADR5ULNGGCGCC0.610.44
194HELD_ALL_ADR5ULNGGCGCC0.90.43
194HELD_FEM_EFFGGCGCC1.051.17
411HELD_ALL_ADR5ULNAAATTT0.531.08
466HELD_FEM_ADRCCCTTT0.511.45
466HELD_MAL_ADR5ULNCCCTTT2.441.06
555HELD_ALL_LIPAAAGGG1.430.7
623HELD_MAL_ADR3ULNCCCTTTnull0
625HELD_FEM_ADR3ULNCCCTTT0.441.32
777HELD_ALL_LIPCCCTTT0.711.34
777HELD_ALL_HDLCCCTTT0.511.8
777HELD_ALL_CC2CCCTTT1.320.9
777HELD_FEM_CC2CCCTTT1.540.81
777HELD_FEM_LIPCCCTTT0.741.28
777HELD_ALL_LIPCCCTTT0.761.23
1005HELD_FEM_LIPAAAGGG0.671.58
1062HELD_ALL_LIP2GGAGAA1.150.85
1275CVD_FEMCCCGGG0.60.73
1275HELD_MAL_CC2CCCGGG1.470.94
1275HELD_MAL_HDLCCCGGG20.88
1275CVD_MALCCCGGG0.721.35
1669HELD_MAL_CC2TTCTCC2.350.47
1669HELD_ALL_CC2TTCTCC1.50.71
1669CVD_ALLTTCTCC1.290.66
1669HELD_MAL_CCTTCTCC3.640.33
1755HELD_MAL_LIP2AAAGGG1.180.81
1765HELD_FEM_LIPAAAGGG1.220.59
2109HELD_FEM_LIP2AAAGGG1.180.88
2150HELD_ALL_LIPTTCTCC1.010.82
2150HELD_ALL_LIPTTCTCC0.980.86
2150HELD_MAL_LIPTTCTCC0.890.61
2150HELD_MAL_LIPTTCTCC0.890.61
2150HELD_FEM_LIPTTCTCC1.060.84
2234HELD_ALL_LIPTTGTGG0.941.3
2321HELD_MAL_LIPGGGTTT0.412.44
2321HELD_MAL_LIPGGGTTT0.412.44
2321HELD_FEM_LIPGGGTTT1.770.6
2354CVD_FEMCCCTTT0.52.02
3451HELD_FEM_ADRCCCTTT0.561.39
3451HELD_MAL_ADR5ULNCCCTTT2.51.04
3452HELD_MAL_ADR5ULNAAAGGG6.920.21
3453HELD_FEM_ADRCCCTTT1.290.95
4912HELD_FEM_LIPGGAGAA1.211.28
5093CVD_FEMGGAGAA0.640.92
5093HELD_MAL_CCGGAGAA2.530.76
6333HELD_MAL_ADR5ULNAAACCC0null
6333HELD_ALL_ADRAAACCC0.631.23
6333HELD_ALL_ADR3ULNAAACCC0.351.59
6333HELD_FEM_ADR3ULNAAACCC0.361.33
6333HELD_ALL_ADR5ULNAAACCC0.292.41
6333HELD_MAL_ADRAAACCC0.511.35
6333CVD_MALAAACCC11.68
7407HELD_ALL_ADR5ULNGGAGAA6.110.45
7407HELD_FEM_ADR5ULNGGAGAA5.60.57
7407HELD_FEM_ADRGGAGAA21.13
7407HELD_FEM_ADR3ULNGGAGAA3.30.83
10584HELD_ALL_ADRGGGTTT0.611.64
10584HELD_FEM_ADRGGGTTT0.551.83
10584HELD_FEM_ADR3ULNGGGTTT0.362.74
11021HELD_FEM_LIPTTCTCC0.711.39
11062HELD_MAL_ADR5ULNTTCTCC4.070.33
11147HELD_FEM_ADRCCCTTT1.071.31
11212HELD_ALL_HDLGGCGCC2.570.72
11371HELD_ALL_ADR3ULNAAAG0.462.15
11371HELD_FEM_ADRAAAG0.611.65
11487HELD_FEM_UEFFTTATAA0.810.99
11585HELD_ALL_LIPGGGTTT1.121.22
11683HELD_FEM_UEFFCCCGGG0.611.71
11863HELD_FEM_VEFFGGAGAA1.480.69
12024HELD_ALL_ADRCCCTTT0.61.67
12024HELD_FEM_ADR3ULNCCCTTT0.333.04
12024HELD_FEM_ADRCCCTTT0.531.88
12024HELD_ALL_ADR3ULNCCCTTT0.392.58
12632HELD_MAL_ADR5ULNCCCTTT0.119
13994CVD_FEMGGAGAA0.43null
13994HELD_MAL_ADRGGAGAAnull0
14090HELD_FEM_EFFCCACAA0.81.29
14159HELD_FEM_EFFTTCTCC1.210.82
14362HELD_FEM_UEFFTTGTGG1.90.59
14410HELD_MAL_ADRGGAG2.590.39
14488HELD_ALL_ADRAAAG0.61.65
14488HELD_FEM_ADRAAAG0.551.83
14488HELD_FEM_ADR3ULNAAAG0.372.69
14490HELD_MAL_ADR5ULNCCCTTTnull0
14490HELD_FEM_ADR5ULNCCCTTT0.362.41
14490HELD_FEM_ADR3ULNCCCTTT0.511.88
14493HELD_ALL_ADRAAAG0.611.64
14493HELD_FEM_ADRAAAG0.551.82
14493HELD_FEM_ADR3ULNAAAG0.362.81
14493HELD_ALL_ADR3ULNAAAG0.412.44
14554HELD_MAL_ADR3ULNCCACAAnull0
14554HELD_MAL_ADR5ULNCCACAAnull0
14554HELD_MAL_ADRCCACAA1.590
14603CVD_MALAAAG0.711.4
14820HELD_FEM_VEFFAAAGGG0.891.32
14820HELD_FEM_UEFFAAAGGG0.891.55
14876HELD_FEM_EFFCCCTTT1.140.8
14876HELD_FEM_VEFFCCCTTT1.270.74
14954HELD_MAL_ADRGGCGCCnull0
14957HELD_FEM_ADR5ULNAAACCCnull0
14957HELD_FEM_VEFFAAACCC0.741.37
14977HELD_FEM_UEFFAAAGGG0.830.88
15349HELD_MAL_ADRCCCTTT1.380.93
15590HELD_ALL_ADR5ULNGGAGAA1.191.76
15590HELD_ALL_ADRGGAGAA0.931.34
15590HELD_FEM_ADRGGAGAA0.921.46
16268HELD_MAL_ADR5ULNCCCGGGnull0
36078HELD_FEM_VEFFAAAG2.490.4
36078HELD_FEM_EFFAAAG1.880.53
36406HELD_FEM_ADR5ULNTTCTCC2.510.75
37135HELD_ALL_ADR3ULNCCCTTT1.430.45
37135HELD_FEM_ADR3ULNCCCTTT1.550.37
37135HELD_FEM_ADR5ULNCCCTTT2.130.28
37135HELD_ALL_ADR5ULNCCCTTT1.880.37
37327HELD_ALL_CC2TTCTCC0.71.27
37327HELD_FEM_VEFFTTCTCC1.350.72
37327HELD_FEM_UEFFTTCTCC1.650.66
37327HELD_MAL_ADRTTCTCC1.450.62
37404HELD_MAL_ADRTTCTCC0.482.04
37413HELD_FEM_ADR5ULNAAATTT0.332.53
37413HELD_FEM_ADR3ULNAAATTT0.452.03
37413HELD_ALL_ADR5ULNAAATTT0.442.08
37413HELD_ALL_ADR3ULNAAATTT0.541.79
37939HELD_FEM_EFFCCCTTT1.050.88
37939CVD_MALCCCTTT0.741.5
38009HELD_ALL_ADRTTGTGG1.330.83
38009HELD_MAL_ADRTTGTGG1.30.93
40004CVD_FEMGGCGCC0.511.61
40522HELD_FEM_ADRTTATAA1.460.77
40522HELD_FEM_ADR3ULNTTATAA1.670.84
40522HELD_FEM_ADR5ULNTTATAA2.040.82
41847HELD_FEM_EFFTTGTGG1.131.13
42084HELD_MAL_ADR5ULNAAACCC0.710.64
42084HELD_FEM_ADR3ULNAAACCC0.522.12
42084HELD_FEM_ADRAAACCC0.741.44
42084HELD_ALL_ADR5ULNAAACCC0.442.14
42084HELD_FEM_ADR5ULNAAACCC0.42.81
42084HELD_ALL_ADR3ULNAAACCC0.571.76
42677HELD_FEM_ADR3ULNCCCGGG1.670.93
42677HELD_FEM_ADR5ULNCCCGGG2.050.84
42677HELD_FEM_ADRCCCGGG1.261.04
46865HELD_FEM_VEFFTTCTCC1.410.75
46865HELD_FEM_EFFTTCTCC1.20.87
46865HELD_ALL_ADR5ULNTTCTCC0.622.09
47856HELD_ALL_ADR5ULNTTCTCC2.240.27
47856HELD_MAL_ADR5ULNTTCTCC5.450.22
47856HELD_FEM_VEFFTTCTCC0.791.24
48490CVD_ALLAAAGGG1.631.05
48490CVD_MALAAAGGG1.570.95
48490HELD_ALL_ADR3ULNAAAGGG0.391.58
48490HELD_FEM_ADR3ULNAAAGGG0.291.66
48490HELD_FEM_ADRAAAGGG0.621.15
50164HELD_FEM_ADR3ULNGGAGAA0.442.23
50164HELD_FEM_ADRGGAGAA0.641.58
50164HELD_ALL_ADR5ULNGGAGAA0.571.4
54704HELD_FEM_ADRGGAGAA0.591.71
54806CVD_ALLGGAGAA0.492.03
54806HELD_FEM_UEFFGGAGAA1.840.47
54807HELD_FEM_ADR5ULNGGAGAA0.272.98
54807HELD_ALL_ADR5ULNGGAGAA0.411.91
54807HELD_FEM_ADRGGAGAA0.61.6
54807HELD_ALL_ADRGGAGAA0.741.33
54807HELD_FEM_ADR3ULNGGAGAA0.511.87
54807HELD_FEM_EFFGGAGAA1.170.9
54807HELD_ALL_ADR3ULNGGAGAA0.611.52
54807HELD_FEM_UEFFGGAGAA1.550.73
55733CVD_MALGGAGAA0.661.5
55733CVD_FEMGGAGAAnull0
55733HELD_FEM_VEFFGGAGAA1.40.73
55733HELD_ALL_ADRGGAGAA1.430.71
55846HELD_FEM_VEFFAAAGGG0.771.12
55846HELD_FEM_UEFFAAAGGG0.71.08
55906HELD_FEM_EFFGGGTTT1.920.93
56084HELD_FEM_UEFFCCCTTT0.116
57818HELD_MAL_ADRGGAGAA0.511.92
57818HELD_ALL_ADRGGAGAA0.661.43
57818HELD_MAL_ADR3ULNGGAGAA0.371.98
57818HELD_ALL_ADR3ULNGGAGAA0.591.4
57818HELD_FEM_EFFGGAGAA0.811.22
57819HELD_MAL_ADRTTCTCC0.581.71
57819HELD_ALL_ADRTTCTCC0.721.38
57819HELD_FEM_EFFTTCTCC0.821.26
57828HELD_FEM_VEFFAAAGGG1.140.74
57987HELD_MAL_ADR5ULNTTCTCC0.346.44
59456HELD_MAL_ADR3ULNAAACCC2.60.51
59460HELD_FEM_UEFFTTCTCC1.161.07
59461HELD_MAL_ADR5ULNCCCTTT7.370
59461HELD_FEM_UEFFCCCTTT1.171.06
59461HELD_FEM_EFFCCCTTT1.150.95
60900HELD_FEM_ADR3ULNAAAGGG0.562.23
60900HELD_MAL_ADRAAAGGG0.641.39
60900HELD_ALL_ADR3ULNAAAGGG0.61.91
60902HELD_MAL_ADRAAATTT1.560.74
60902HELD_ALL_ADRAAATTT1.270.88
60934CVD_ALLCCCTTT1.60.83
60934CVD_MALCCCTTT1.410.86
60934HELD_MAL_ADRCCCTTT0.920.78
60934CVD_FEMCCCTTT1.930.77
60957HELD_MAL_ADR5ULNGGAGAAnull0
60957HELD_MAL_ADR3ULNGGAGAA3.290.35
60959HELD_MAL_ADR3ULNTTCTCC0.151.34
60959HELD_MAL_ADR5ULNTTCTCC02.56
60959HELD_ALL_ADR3ULNTTCTCC0.531.14
60959HELD_ALL_ADRTTCTCC0.820.98
60959HELD_MAL_ADRTTCTCC0.820.86
60962HELD_MAL_ADR5ULNCCCTTT0.190.89
60962HELD_MAL_ADR3ULNCCCTTT0.22.58
60962HELD_MAL_ADRCCCTTT0.651.3
60974HELD_FEM_ADR5ULNGGAGAA1.340.44
60978HELD_MAL_ADRGGCGCC2.650.41
60978HELD_FEM_EFFGGCGCC1.160.82
60978HELD_FEM_VEFFGGCGCC1.280.73
60999HELD_MAL_ADR5ULNGGGTTTnull0
61011CVD_MALTTCTCC0.711.54
61011HELD_FEM_EFFTTCTCC0.970.95
61086HELD_MAL_ADRGGAGAA1.780.64
61126HELD_MAL_ADRCCCTTT1.250.61
61126HELD_FEM_VEFFCCCTTT0.681.22
61126HELD_FEM_UEFFCCCTTT0.511.65
61126HELD_FEM_EFFCCCTTT0.811.12
61137HELD_ALL_ADRTTCTCC0.751.31
61147HELD_FEM_EFFGGAGAA0.980.88
61176HELD_MAL_ADR5ULNAAAGGG5.590.3
61176HELD_MAL_ADRAAAGGG1.630.65
61176HELD_MAL_ADR3ULNAAAGGG2.880.34
61176HELD_ALL_ADR5ULNAAAGGG2.090.37
61184HELD_MAL_ADR5ULNCCCTTT4.170
61184HELD_MAL_ADRCCCTTT1.640.6
61197HELD_MAL_ADR3ULNAAAGGG0.580.99
61270HELD_MAL_ADR3ULNAAAGGG0.263.79
61270HELD_MAL_ADR5ULNAAAGGG0.175.83
61270HELD_ALL_CC2AAAGGG1.880.53
61272HELD_MAL_ADR5ULNAAAGGG0.471.37
61272HELD_FEM_ADRAAAGGG1.570.62
61284HELD_FEM_EFFGGAGAA1.020.82
61292HELD_FEM_EFFGGAGAA0.890.94
61292HELD_MAL_ADRGGAGAA0.751.57
61297CVD_ALLTTCTCC0.781.19
61324HELD_FEM_VEFFGGAGAA1.650.88
61328HELD_FEM_EFFAAAGGG0.52
61373HELD_FEM_ADRGGCGCC1.570.73
61373HELD_ALL_ADRGGCGCC1.350.78
900066HELD_MAL_LIPCCCTTT2.170
900071HELD_FEM_UEFFGGCGCC1.11.55
900072HELD_FEM_UEFFGGCGCC1.561.09
900072HELD_FEM_HDLGGCGCC0.321.78
900072HELD_FEM_VEFFGGCGCC1.230.98
900073HELD_ALL_ADRGGCGCC0.711.29
900073HELD_MAL_ADRGGCGCC0.581.57
900073HELD_ALL_CC2GGCGCC1.290.78
900073HELD_MAL_ADR3ULNGGCGCC0.441.49
900073HELD_FEM_EFFGGCGCC0.851.12
900074HELD_FEM_LIPCCCTTT0.671.25
900074HELD_FEM_UEFFCCCTTT1.370.98
900083HELD_FEM_EFFAAAGGG0.851.03
900115HELD_MAL_ADR3ULNAAAGGG0.630.52
900115HELD_ALL_CCAAAGGG0.591.48
900115HELD_ALL_ADR5ULNAAAGGG0.620.86
900143HELD_MAL_ADR5ULNGGGTTT0null
900143HELD_ALL_ADRGGGTTT0.651.15
900143HELD_FEM_ADR3ULNGGGTTT0.351.25
900143HELD_ALL_ADR3ULNGGGTTT0.371.43
900143HELD_ALL_ADR5ULNGGGTTT0.32.21
900143HELD_FEM_ADRGGGTTT0.721.05
900173HELD_MAL_ADR3ULNTTGTGG4.040.3
900174HELD_MAL_ADR3ULNAAAGGG0.420.67
900174HELD_MAL_ADR5ULNAAAGGG0.240.64
900174HELD_ALL_ADR5ULNAAAGGG0.560.84
900174HELD_FEM_CCAAAGGG0.481.75
900174HELD_ALL_CCAAAGGG0.591.45
900175HELD_FEM_EFFGGAGAA2.670.48
900180CVD_ALLGGAGAA0.570.96
900180CVD_FEMGGAGAA0.231.06
900180HELD_MAL_CCGGAGAA0.320.96
900180HELD_ALL_CCGGAGAA0.610.8
900221HELD_MAL_ADRGGCGCC1.251.16
900250HELD_MAL_ADR5ULNCCCTTT0.451.01
900342HELD_ALL_ADRGGAGAA0.71.43
900342HELD_FEM_ADRGGAGAA0.641.56
900344HELD_FEM_ADRAAACCC0.551.12
900344HELD_FEM_ADR3ULNAAACCC0.511.03
900344HELD_ALL_ADRAAACCC0.751.02
900344HELD_FEM_ADR5ULNAAACCC0.411.26
10000001HELD_MAL_LIPGGAGAA3.130.33
10000001HELD_ALL_LIPGGAGAA1.410.95
10000002HELD_ALL_LIPAAAGGG1.430.74
10000017HELD_ALL_LIPTTCTCC0.721.49
BAYSNPRR3FQ1_AFQ2_AFQ3_AFQ1_BFQ2_BFQ3_B
1602.437622289
1943.59347213310
1943668406518
1940.7281128408011467
4111.966137496017
4661.05104120242718
4660540172415
5551.02453913356515
623016005261
6251.7617827288
7771.516532586222
7772.3914912750
7770.285616134145
777029801893
7771.545327458161
7771.576429587252
10050.62592416482
10621.194741361550719512
12751.896717761
12750.22182216166
12750.48824128
12751.112116141424
1669037401891
16690.427620140243
16691.557218647261
1669013101251
17551.041431016213414566
17651.54136922345
21090.79217871222211720
21502.266526776390
21502.176728774370
21503.25133326100
21503.25133326100
21502.055223450290
22340.5242526494317
2321null12603230
2321null12603230
23210746065131
2354null221303640
34511.03114220232818
34510540182616
3452081029256
34530.536314263211
49120.7334102623532
50931.89121118165
50930.3641386
63330080192312
63331.19256435444825
63331.3662513444825
63331.6441410252513
63330.973165444825
63331.1683316192312
63330.37821381311
74070.9823313019
74070.692320149
74070.5841850149
74070.63730149
10584null12112012730
10584null63706910
10584null26306910
110211.265523259111
11062062022315
111470.4219374162713
112120.35541285
11371null417012360
11371null65806920
114872.532720544280
115850.62286115255431
116830.892825355185
118630134200115341
12024null12113012830
12024null25407010
12024null63807010
12024null415012830
12632null8106400
139942.3228023700
13994052004811
140900.84191735219497
141591.04120125479415544
143620525063142
14410null59205580
14488null12012012830
14488null64707010
14488null27307010
14490090036193
144902.6979151191
144901.671515151191
14493null12213012530
14493null65806810
14493null27406810
14493null435012530
145540160049111
14554080049111
145540.67550649111
14603null30901200
148200.69656715714526
148200.524265372217
148761.21111118519615237
148761.14605928438022
14954059006311
14957null170067110
149570.98118291127151
149772.092918945282
153490.5527275203213
155900.159151446135
155900.66377518446135
155900.59204110243022
16268090048161
36078null1930980
36078null275016100
3640601070233714
371351.69191213376119
371351.6313610183112
371351.5935183112
371351.551266376119
373271.23764300
373271804617516115
373270.673317328347
373270.714311131216
374042.0246214900
374134.8179146150
374133.11415146150
374133.021310190261
374131.822618190261
379392.03254365253450
379390.67251011201
380090.429628275347
3800904413037144
400042.078721330
405220.6645226343212
405220.2519111343212
4052201160343212
418470.687910835679561
4208410.3351144120
4208401714048122
4208404526048122
420841.941410192242
42084099048122
420841.192817192242
426770.3513152153113
426770.28881153113
426770.5525376153113
468650.5910146472629
468650.7517687915510615
46865011150774910
478561.572033815210
47856081036263
478561.1680621197468
484900.541621941516
484900.5812135287
484901.2262912446328
484901.323198253314
484901.27133720253314
501641.77201016791
501641.01532116791
501643.421772112282
54704null571105820
54806null30403100
548062.4475155180
548072.7778256122
548072.761211393324
548071.344027456122
548071.197751693324
548071.671811256122
548070.691898391609116
548071.622718393324
5480704112043233
557331.3925811300
55733null15001240
557330134210116331
557330.67117181107312
558461.35555922765513
558461.6421201142277
55906015110172311
560841.291611642
578181.55402035951
578181.7296375121201
578183.5112325951
578183.135103121201
578181.26223635245453
578191.253523353102
578191.2186437111275
578190.83200845224587
578281.39556529468715
579870180193313
594560.4495117309
5946002429030407
594610.64801302311
5946102726034367
594610.761471122112912033
609000.34821126237
609001.321926628163
609000.5415262543910
609020.483615225226
609020.672375584311
609340.552917681410
609340.6420124364
609341.8126231329313
609340.48952586
60957080035192
609570142035192
60959319522285
609592.6706222285
609591.6492412425617
609591.31356031425617
609591.6218251522285
609621011227112
609623.2125227112
609621.591714527112
609743.96123247271
609780603053111
609782.02255363247500
609781.96137202120310
60999null90050140
610110241401201
610111.641968013196853
610860327022122
611261.5723221416355
611261.15338633516323
611261.02103410293013
611261.1176140589812147
611371.2481493103352
611471.281011335910515338
61176062016318
611760.833020616318
611760.87104216318
611761.351664465813
611842.0680138203
611840.794910238203
611974.07104347151
61270null7904690
61270null3504690
61270null1520120
61272934133230
612720.955016332273
612841.321041216510315240
612921.361001335511814531
612920.621365302311
612971.2853281146144
613240.581254557
6132822751127600
6137306114050224
613730.58110242100365
9000661.515022372
9000710.4713318173228
9000720.516187142523
9000720.9621679108
9000720.8445326305134
9000731.2745681264507
9000731.231737530223
900073null1970020
9000732.3659330223
9000731.161321342915811922
9000741.3119471029355
9000740.5323245253717
9000831.16811346610012951
9001153.3945722307
9001151.31524624133
9001152.487117536314
9001430070182312
9001431.26256235435123
9001431.841510252811
9001431.4962413435123
9001431.063165435123
9001431.33173119252811
9001730142031213
9001743.7636722275
9001745.8913422275
9001742.68697485213
9001741.1971741362
9001741.31323621133
90017509309112
9001801.4124545213418
9001801.8121417141610
9001802.68266981
9001801.847191813225
9002210.5120286142315
9002506.1952245131
9003421.157138489213
9003421.23722349102
9003441.55153223322911
9003441.9781412322911
9003441.34345935495721
9003442.01496322911
100000011.049625274
100000010.58365410246224
100000020.7764308504613
100000170.517625194133

TABLE 6b
Correlation of PA SNP alleles to relative risk
For diagnostic conclusions to be drawn from genotyping a particular
patient we calculated the relative risks RR1, and RR2 for the two
possible alleles of each SNP. Given the allele frequencies as
allele1allele2
caseN11N12
controlN21N22

we calculate RR 1=N 11N 21/N 12N 22 RR 2=N 12N 22/N 11N 21

Here, the case and control populations represent any case-control-group pair, or bad (case)-good (control)-group pair, respectively (due to their increased response to statins, ‘high responders’ are treated as a case cohort, whereas ‘low responders’ are treated as the respective control cohort). A value RR1>1, and RR2>1 indicates an increased risk for individuals carrying allele 1, and allele2, respectively. For example, RR1=3 indicates a 3-fold risk of an individual carrying allele 1 as compared to individuals not carrying allele 1 (a detailed description of relative risk calculation and statistics can be found in (Biostatistics, L. D. Fisher and G. van Belle, Wiley Interscience 1993)). The baySNP number refers to an internal numbering of the PA SNPs and can be found in the sequence listing. null: not defined.

BAYSNPALLELE1ALLELE2COMPARISONRR1RR2SIZE_A
160TCHELD_MAL_ADR3ULN0.521.9116
194GCHELD_FEM_ADR5ULN0.462.1514
194GCHELD_ALL_ADR5ULN0.621.6220
194GCHELD_FEM_EFF1.130.89249
411ATHELD_ALL_ADR5ULN0.611.6326
466CTHELD_FEM_ADR0.81.2571
466CTHELD_MAL_ADR5ULN2.820.359
555AGHELD_ALL_LIP1.20.8397
623CTHELD_MAL_ADR3ULNnull016
625CTHELD_FEM_ADR3ULN0.611.6431
777CTHELD_ALL_LIP0.741.36102
777CTHELD_ALL_HDL0.561.7824
777CTHELD_ALL_CC21.420.773
777CTHELD_FEM_CC21.710.5837
777CTHELD_FEM_LIP0.761.3284
777CTHELD_ALL_LIP0.771.398
1005AGHELD_FEM_LIP0.751.3484
1062GAHELD_ALL_LIP21.10.91625
1275CGCVD_FEM0.581.7230
1275CGHELD_MAL_CC21.460.6841
1275CGHELD_MAL_HDL1.820.5518
1275CGCVD_MAL0.811.2451
1669TCHELD_MAL_CC22.380.4241
1669TCHELD_ALL_CC21.470.6897
1669TCCVD_ALL1.110.996
1669TCHELD_MAL_CC3.860.2614
1755AGHELD_MAL_LIP21.080.93306
1765AGHELD_FEM_LIP0.761.3186
2109AGHELD_FEM_LIP21.160.86316
2150TCHELD_ALL_LIP0.891.1398
2150TCHELD_ALL_LIP0.881.14102
2150TCHELD_MAL_LIP0.671.4919
2150TCHELD_MAL_LIP0.671.4919
2150TCHELD_FEM_LIP0.961.0479
2234TGHELD_ALL_LIP1.080.92100
2321GTHELD_MAL_LIP0.462.1618
2321GTHELD_MAL_LIP0.462.1618
2321GTHELD_FEM_LIP1.810.5580
2354CTCVD_FEM0.561.7835
3451CTHELD_FEM_ADR0.831.2173
3451CTHELD_MAL_ADR5ULN2.860.359
3452AGHELD_MAL_ADR5ULN6.460.159
3453CTHELD_FEM_ADR1.310.7671
4912GAHELD_FEM_LIP1.280.7870
5093GACVD_FEM0.651.5532
5093GAHELD_MAL_CC2.310.4311
6333ACHELD_MAL_ADR5ULN0.81.258
6333ACHELD_ALL_ADR0.791.27124
6333ACHELD_ALL_ADR3ULN0.621.644
6333ACHELD_FEM_ADR3ULN0.571.7628
6333ACHELD_ALL_ADR5ULN0.661.5124
6333ACHELD_MAL_ADR0.771.357
6333ACCVD_MAL1.290.7832
7407GAHELD_ALL_ADR5ULN1.540.658
7407GAHELD_FEM_ADR5ULN1.860.547
7407GAHELD_FEM_ADR1.390.7227
7407GAHELD_FEM_ADR3ULN1.670.613
10584GTHELD_ALL_ADR0.621.61133
10584GTHELD_FEM_ADR0.561.7970
10584GTHELD_FEM_ADR3ULN0.382.6529
11021TCHELD_FEM_LIP0.751.3380
11062TCHELD_MAL_ADR5ULN3.380.38
11147CTHELD_FEM_ADR1.220.8260
11212GCHELD_ALL_HDL2.150.4610
11371AGHELD_ALL_ADR3ULN0.482.0648
11371AGHELD_FEM_ADR0.621.6173
11487TAHELD_FEM_UEFF0.751.3352
11585GTHELD_ALL_LIP1.20.83104
11683CGHELD_FEM_UEFF0.741.3656
11863GAHELD_FEM_VEFF1.460.68154
12024CTHELD_ALL_ADR0.611.64134
12024CTHELD_FEM_ADR3ULN0.352.8929
12024CTHELD_FEM_ADR0.551.8271
12024CTHELD_ALL_ADR3ULN0.42.4946
12632CTHELD_MAL_ADR5ULN0.128.539
13994GACVD_FEM0.432.3230
13994GAHELD_MAL_ADRnull052
14090CAHELD_FEM_EFF0.851.18269
14159TCHELD_FEM_EFF1.090.92292
14362TGHELD_FEM_UEFF2.010.557
14410GAHELD_MAL_ADR2.520.461
14488AGHELD_ALL_ADR0.621.62132
14488AGHELD_FEM_ADR0.561.7971
14488AGHELD_FEM_ADR3ULN0.382.6130
14490CTHELD_MAL_ADR5ULNnull09
14490CTHELD_FEM_ADR5ULN0.462.1517
14490CTHELD_FEM_ADR3ULN0.611.6531
14493AGHELD_ALL_ADR0.621.61135
14493AGHELD_FEM_ADR0.561.7773
14493AGHELD_FEM_ADR3ULN0.372.6931
14493AGHELD_ALL_ADR3ULN0.422.3648
14554CAHELD_MAL_ADR3ULNnull016
14554CAHELD_MAL_ADR5ULNnull08
14554CAHELD_MAL_ADR1.540.6561
14603AGCVD_MAL0.741.3539
14820AGHELD_FEM_VEFF1.030.97147
14820AGHELD_FEM_UEFF1.110.955
14876CTHELD_FEM_EFF1.010.99280
14876CTHELD_FEM_VEFF1.080.93147
14954GCHELD_MAL_ADRnull059
14957ACHELD_FEM_ADR5ULNnull017
14957ACHELD_FEM_VEFF0.771.3148
14977AGHELD_FEM_UEFF0.741.3556
15349CTHELD_MAL_ADR1.360.7459
15590GAHELD_ALL_ADR5ULN1.580.6325
15590GAHELD_ALL_ADR1.090.92130
15590GAHELD_FEM_ADR1.130.8971
16268CGHELD_MAL_ADR5ULNnull09
36078AGHELD_FEM_VEFF2.240.4522
36078AGHELD_FEM_EFF1.750.5732
36406TCHELD_FEM_ADR5ULN2.520.417
37135CTHELD_ALL_ADR3ULN0.971.0344
37135CTHELD_FEM_ADR3ULN1.010.9929
37135CTHELD_FEM_ADR5ULN1.250.817
37135CTHELD_ALL_ADR5ULN1.180.8524
37327TCHELD_ALL_CC20.771.317
37327TCHELD_FEM_VEFF1.190.84143
37327TCHELD_FEM_UEFF1.480.6853
37327TCHELD_MAL_ADR1.430.755
37404TCHELD_MAL_ADR0.492.0449
37413ATHELD_FEM_ADR5ULN0.422.3917
37413ATHELD_FEM_ADR3ULN0.541.8530
37413ATHELD_ALL_ADR5ULN0.52.0224
37413ATHELD_ALL_ADR3ULN0.611.6445
37939CTHELD_FEM_EFF0.981.02295
37939CTCVD_MAL0.831.236
38009TGHELD_ALL_ADR1.360.73126
38009TGHELD_MAL_ADR1.440.757
40004GCCVD_FEM0.561.7817
40522TAHELD_FEM_ADR1.40.7273
40522TAHELD_FEM_ADR3ULN1.750.5731
40522TAHELD_FEM_ADR5ULN2.260.4417
41847TGHELD_FEM_EFF1.190.84222
42084ACHELD_MAL_ADR5ULN0.52.027
42084ACHELD_FEM_ADR3ULN0.661.5231
42084ACHELD_FEM_ADR0.841.271
42084ACHELD_ALL_ADR5ULN0.511.9425
42084ACHELD_FEM_ADR5ULN0.561.818
42084ACHELD_ALL_ADR3ULN0.641.5646
42677CGHELD_FEM_ADR3ULN1.610.6230
42677CGHELD_FEM_ADR5ULN1.890.5317
42677CGHELD_FEM_ADR1.270.7968
46865TCHELD_FEM_VEFF1.360.74151
46865TCHELD_FEM_EFF1.180.85272
46865TCHELD_ALL_ADR5ULN0.861.1626
47856TCHELD_ALL_ADR5ULN1.510.6626
47856TCHELD_MAL_ADR5ULN4.880.29
47856TCHELD_FEM_VEFF0.841.2153
48490AGCVD_ALL1.540.6546
48490AGCVD_MAL1.480.6830
48490AGHELD_ALL_ADR3ULN0.691.4447
48490AGHELD_FEM_ADR3ULN0.631.5830
48490AGHELD_FEM_ADR0.771.2970
50164GAHELD_FEM_ADR3ULN0.52.0131
50164GAHELD_FEM_ADR0.71.4475
50164GAHELD_ALL_ADR5ULN0.551.8326
54704GAHELD_FEM_ADR0.611.6468
54806GACVD_ALL0.511.9734
54806GAHELD_FEM_UEFF1.560.6453
54807GAHELD_FEM_ADR5ULN0.352.8417
54807GAHELD_ALL_ADR5ULN0.462.1626
54807GAHELD_FEM_ADR0.671.4871
54807GAHELD_ALL_ADR0.791.26134
54807GAHELD_FEM_ADR3ULN0.571.7631
54807GAHELD_FEM_EFF1.170.85281
54807GAHELD_ALL_ADR3ULN0.661.5148
54807GAHELD_FEM_UEFF1.580.6353
55733GACVD_MAL0.691.4534
55733GACVD_FEMnull015
55733GAHELD_FEM_VEFF1.390.72155
55733GAHELD_ALL_ADR1.390.72136
55846AGHELD_FEM_VEFF0.81.25136
55846AGHELD_FEM_UEFF0.711.4152
55906GTHELD_FEM_EFF2.130.4726
56084CTHELD_FEM_UEFF0.362.758
57818GAHELD_MAL_ADR0.571.7663
57818GAHELD_ALL_ADR0.681.46138
57818GAHELD_MAL_ADR3ULN0.362.7817
57818GAHELD_ALL_ADR3ULN0.561.848
57818GAHELD_FEM_EFF0.831.21291
57819TCHELD_MAL_ADR0.661.5261
57819TCHELD_ALL_ADR0.761.31136
57819TCHELD_FEM_EFF0.861.16289
57828AGHELD_FEM_VEFF0.961.04149
57987TCHELD_MAL_ADR5ULN1.030.979
59456ACHELD_MAL_ADR3ULN2.080.4815
59460TCHELD_FEM_UEFF1.250.853
59461CTHELD_MAL_ADR5ULN3.80.269
59461CTHELD_FEM_UEFF1.270.7953
59461CTHELD_FEM_EFF1.140.87280
60900AGHELD_FEM_ADR3ULN0.861.1630
60900AGHELD_MAL_ADR0.741.3551
60900AGHELD_ALL_ADR3ULN0.821.2243
60902ATHELD_MAL_ADR1.530.6653
60902ATHELD_ALL_ADR1.270.79114
60934CTCVD_ALL1.550.6452
60934CTCVD_MAL1.380.7236
60934CTHELD_MAL_ADR0.81.2562
60934CTCVD_FEM1.810.5516
60957GAHELD_MAL_ADR5ULNnull08
60957GAHELD_MAL_ADR3ULN3.150.3216
60959TCHELD_MAL_ADR3ULN0.42.5215
60959TCHELD_MAL_ADR5ULN0.372.718
60959TCHELD_ALL_ADR3ULN0.661.5145
60959TCHELD_ALL_ADR0.841.2126
60959TCHELD_MAL_ADR0.781.2958
60962CTHELD_MAL_ADR5ULN0.185.674
60962CTHELD_MAL_ADR3ULN0.323.089
60962CTHELD_MAL_ADR0.691.4536
60974GAHELD_FEM_ADR5ULN0.941.0717
60978GCHELD_MAL_ADR2.730.3763
60978GCHELD_FEM_EFF1.10.91294
60978GCHELD_FEM_VEFF1.190.84159
60999GTHELD_MAL_ADR5ULNnull09
61011TCCVD_MAL0.821.2138
61011TCHELD_FEM_EFF0.921.08289
61086GAHELD_MAL_ADR1.840.5439
61126CTHELD_MAL_ADR0.961.0459
61126CTHELD_FEM_VEFF0.821.21152
61126CTHELD_FEM_UEFF0.771.2954
61126CTHELD_FEM_EFF0.881.13274
61137TCHELD_ALL_ADR0.81.25133
61147GAHELD_FEM_EFF0.921.09293
61176AGHELD_MAL_ADR5ULN4.450.228
61176AGHELD_MAL_ADR1.380.7256
61176AGHELD_MAL_ADR3ULN1.90.5316
61176AGHELD_ALL_ADR5ULN1.410.7126
61184CTHELD_MAL_ADR5ULN20.59
61184CTHELD_MAL_ADR1.510.6661
61197AGHELD_MAL_ADR3ULN0.492.0517
61270AGHELD_MAL_ADR3ULN0.372.716
61270AGHELD_MAL_ADR5ULN0.283.648
61270AGHELD_ALL_CC21.780.5617
61272AGHELD_MAL_ADR5ULN0.492.058
61272AGHELD_FEM_ADR1.40.7169
61284GAHELD_FEM_EFF0.921.09290
61292GAHELD_FEM_EFF0.861.16288
61292GAHELD_MAL_ADR0.961.0462
61297TCCVD_ALL0.81.2492
61324GAHELD_FEM_VEFF1.620.6221
61328AGHELD_FEM_EFF0.52277
61373GCHELD_FEM_ADR1.660.675
61373GCHELD_ALL_ADR1.340.74136
900066CTHELD_MAL_LIP1.360.7417
900071GCHELD_FEM_UEFF1.330.7552
900072GCHELD_FEM_UEFF1.560.6441
900072GCHELD_FEM_HDL0.781.2925
900072GCHELD_FEM_VEFF1.190.84123
900073GCHELD_ALL_ADR0.81.25125
900073GCHELD_MAL_ADR0.741.3559
900073GCHELD_ALL_CC21.230.8126
900073GCHELD_MAL_ADR3ULN0.541.8517
900073GCHELD_FEM_EFF0.881.13295
900074CTHELD_FEM_LIP0.81.2576
900074CTHELD_FEM_UEFF1.380.7352
900083AGHELD_FEM_EFF0.881.13281
900115AGHELD_MAL_ADR3ULN0.52.0216
900115AGHELD_ALL_CC0.721.3945
900115AGHELD_ALL_ADR5ULN0.61.6725
900143GTHELD_MAL_ADR5ULN0.821.227
900143GTHELD_ALL_ADR0.781.28122
900143GTHELD_FEM_ADR3ULN0.551.8129
900143GTHELD_ALL_ADR3ULN0.611.6343
900143GTHELD_ALL_ADR5ULN0.651.5324
900143GTHELD_FEM_ADR0.781.2867
900173TGHELD_MAL_ADR3ULN3.850.2616
900174AGHELD_MAL_ADR3ULN0.412.4316
900174AGHELD_MAL_ADR5ULN0.293.488
900174AGHELD_ALL_ADR5ULN0.551.8322
900174AGHELD_FEM_CC0.691.4528
900174AGHELD_ALL_CC0.731.3842
900175GAHELD_FEM_EFF2.520.412
900180GACVD_ALL0.721.38102
900180GACVD_FEM0.511.9733
900180GAHELD_MAL_CC0.432.3114
900180GAHELD_ALL_CC0.641.5544
900221GCHELD_MAL_ADR1.330.7554
900250CTHELD_MAL_ADR5ULN0.372.749
900342GAHELD_ALL_ADR0.751.33113
900342GAHELD_FEM_ADR0.711.4262
900344ACHELD_FEM_ADR0.661.5170
900344ACHELD_FEM_ADR3ULN0.571.7534
900344ACHELD_ALL_ADR0.81.26128
900344ACHELD_FEM_ADR5ULN0.531.8919
10000001GAHELD_MAL_LIP1.770.5617
10000001GAHELD_ALL_LIP1.330.75100
10000002AGHELD_ALL_LIP1.330.75102
10000017TCHELD_ALL_LIP0.81.25102
BAYSNPFREQ1_AFREQ2_ASIZE_BFREQ1_BFREQ2_B
1601319597246
1941018647553
1941822123145101
194290208261274248
411252712615894
4666181697563
466144565854
5551296511513595
623320591108
6252933638244
7771624211019426
777371132595
77712818538224
777668304515
777133357513218
7771573911419929
1005142267413612
106210841667141209219
1275194114208
12755824282828
12752412242028
12755844203010
1669784284511
1669172226710430
1669162307412028
166927118297
1755387225345413277
1765211517027113
2109521111359561157
21501564011519139
21501624211118537
2150299366210
2150299366210
2150127317912929
22341366410914177
232130635673
232130635673
232115467914315
2354571340764
34516482697464
3451144606258
3452171608337
345310339698454
49127862605169
50933034395226
5093166171420
633388546147
633311413411713698
6333375111713698
63332234637551
6333222611713698
63334965546147
63333727322935
740779503268
740777231432
74072628231432
74071313231432
10584254121302573
105841337701391
10584553701391
11021133277112913
11062142587541
111477545565953
11212146151218
113718971292526
113711388711402
1148774307211628
1158511791110104116
1168381317812828
118632882015026436
12024255131312593
12024544711411
120241348711411
120248751312593
12632171641280
1399456437740
13994104050973
140904558327548763
14159365219293343243
1436210957914018
144101202631188
14488252121312593
144881357711411
14488573711411
14490180589125
1449023117112121
1449045177112121
14493257131282533
144931388691371
14493584691371
144939151282533
14554320619923
14554160619923
1455411012619923
1460369912240
148201979714218797
148207436769656
14876340220285344226
14876179115145166124
149541180651273
149573407814511
149572653114326917
1497776367511832
153498137657258
155903317140149131
15590149111140149131
155908161767874
162681806511218
3607841317268
36078595264210
36406277748365
37135503811713599
371353226616755
371352113616755
37135301811713599
373272014360
373272068012716391
373278323699048
373278723496434
3740494449980
3741323116110715
3741343176110715
37413361211720628
37413702011720628
379395444629855145
37939601213242
380092203211618448
3800910113558822
40004231116293
40522112347810056
4052249137810056
405222867810056
41847266178223229217
420841135610012
4208448146210816
42084116266210816
42084381211820828
420842796210816
42084731911820828
426774119596157
426772410596157
426778749596157
468652485414320680
46865439105276416136
46865371513620369
4785643914321472
47856171659832
478562228415124062
484905339352347
484903723171222
484904153135151119
484902535728361
484906377728361
5016450127714311
50164127237714311
50164411114225232
5470412511601182
5480664431620
548069977312818
5480722127012416
54807351712921840
54807107357012416
548072056312921840
5480747157012416
54807461101267411123
54807722412921840
5480794126910929
55733581013260
5573330016284
557332892115026535
557332522014024535
5584616910314420781
5584662427611141
559064111515745
560848822368
5781810026651237
578182294714226222
57818277651237
57818801614226222
578185097329353551
5781993296511614
578192155714324937
578194849428950672
57828175123148179117
57987108657159
59456237566448
5946077297710054
59461162648345
5946180267710450
59461406154282378186
609003723567537
609006438477222
60900563010314759
609028719537234
609021814711215965
609347529323034
609345220131214
609347549638937
60934239191820
60957160568923
60957302568923
609591119557238
60959610557238
60959424811514090
6095913012211514090
609596155557238
6096235406515
6096299406515
609624824406515
609742777512129
6097812336511713
609785464229754450
609782942415127131
609991806411414
61011621413242
6101147210628447791
61086717365616
611266850566745
61126152152137165109
611265454728856
61126292256266317215
611372115514024139
61147335251296363229
61176142556347
611768032556347
61176248556347
61176381411715084
61184162619626
6118410814619626
6119724106310917
61270239551019
61270115551019
61270322342
61272106568923
6127211622629133
61284329251295358232
61292333243294381207
612927846648345
61297134506410622
613242913171519
6132855132765520
61373136147612230
613732442814123646
900066304325311
9000715747776688
9000725032625371
9000722030272826
900072141105115111119
9000731589212117864
9000737147558228
900073457222
9000731915558228
900073398192299435163
9000748567699345
9000747034798771
900083296266280329231
9001151319597444
9001155436406119
900115252513016991
90014377535947
90014311213211713797
9001432335647850
900143365011713797
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9001436569647850
900173302558327
9001741220547137
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900174212311314878
9001743125213210
9001744935375519
900175213222915
90018069135737670
9001801848404436
9001801018182610
9001803355404832
9002216840525153
9002501265910315
9003421804611319927
90034296286110814
9003446278729351
9003443038729351
90034412712912715599
9003441721729351
100000012410363735
1000000112674110110110
100000021584610914672
100000171772711020119